Sustained release formulations of nalbuphine

ABSTRACT

Sustained release formulations of nalbuphine or pharmaceutically acceptable salts thereof; methods for making the sustained release formulations of nalbuphine or pharmaceutically acceptable salts thereof; and methods for using the sustained release formulations of nalbuphine or pharmaceutically acceptable salts thereof to treat patients suffering from pain are provided.

FIELD OF THE INVENTION

The invention provides sustained release formulations of nalbuphine andpharmaceutically acceptable salts thereof; methods for making thesustained release formulations of nalbuphine and pharmaceuticallyacceptable salts thereof; and methods for using the sustained releaseformulations of nalbuphine and pharmaceutically acceptable salts thereofto treat patients suffering from pain.

BACKGROUND OF THE INVENTION

Pain is the most frequently reported symptom and it is a common clinicalproblem that confronts the clinician. Many millions of people in theUnited States suffer from pain that is chronically undertreated orinappropriately managed. The clinical usefulness of the analgesicproperties of opioids has been recognized for centuries, and morphineand its derivatives have been widely used for analgesia for decades in avariety of clinical pain states.

Nalbuphine HCl (17-(cyclobutylmethyl)-4,5α-epoxymorphinan-3,6α,14-triolhydrochloride) is a synthetic opioid agonist-antagonist analgesicbelonging to the phenanthrene class of opioids. Nalbuphine is related tothe opioid antagonist, naloxone, and also to the opioid analgesic,oxymorphone. Nalbuphine HCl is marketed in the United States under thetrade name Nubain® by Endo Pharmaceuticals and is primarily a kappaagonist/partial mu antagonist analgesic.

Although oral administration of nalbuphine has been studied (Lo, M W etal. The Disposition and Bioavailability of Intravenous and OralNalbuphine in Healthy Volunteers, J. Clin. Pharmacol. 27:866-873 (1987);Aitkenhead, A R et al. “The Pharmacokinetics of Oral and IntravenousNalbuphine in Healthy Volunteers, Br. J. Clin. Pharmacol. 25:264-288(1988); Jaillon P, et al. Pharmacokinetics of Nalbuphine in Infants,Young Healthy Volunteers, and Elderly Patients, Clin. Pharmacol. Ther.46:226-233 (1989)), it has never received marketing approval. Currently,nalbuphine is marketed only as an injection (10 mg/ml in 10 ml multipledose vials; 20 mg/ml in 10 ml multiple dose vials; 10 mg/ml in 1 mlampules; 20 mg/ml in 1 ml ampules) for intramuscular, subcutaneous, andintravenous administration.

The dosing interval of nalbuphine injection is approximately every threeto six hours. Although the half-life following oral administration ofimmediate release nalbuphine has been reported to be somewhat longer(approximately five to seven hours), the drug effect generally wears offtoward the end of the therapeutic window.

SUMMARY OF THE INVENTION

The invention provides compositions including nalbuphine or apharmaceutically acceptable salt thereof and a sustained releasedelivery system. The sustained release delivery system includes at leastone hydrophilic compound, at least one cross-linking agent and at leastone pharmaceutical diluent. The sustained release delivery system mayfurther include one or more additional cross-linking compounds.

The invention also provides compositions including nalbuphine or apharmaceutically acceptable salt thereof and a sustained releasedelivery system. The sustained release delivery system includes at leastone hydrophilic compound, at least one cationic cross-linking compound,and at least one pharmaceutical diluent. The sustained release deliverysystem may further include one or more additional cross-linkingcompounds.

The invention further provides multilayer compositions includingnalbuphine or a pharmaceutically acceptable salt thereof and a sustainedrelease delivery system. The formulation includes a first layer and asecond layer. The first layer includes an immediate release formulationof nalbuphine hydrochloride or a pharmaceutically acceptable saltthereof, while the second layer includes an extended release formulationof nalbuphine or a pharmaceutically acceptable salt of nalbuphine. Inthis aspect, the first layer includes nalbuphine or a pharmaceuticallyacceptable salt of nalbuphine and the second layer includes nalbuphineor a pharmaceutically acceptable salt of nalbuphine and a sustainedrelease delivery system. The first layer optionally includes a sustainedrelease delivery system. In one embodiment, the second layer includesabout 45 mg nalbuphine or a pharmaceutically acceptable salt ofnalbuphine and about 110 mg to about 150 mg of a sustained releasedelivery system; and the first layer includes from about 10 mg to about20 mg nalbuphine or a pharmaceutically acceptable salt of nalbuphineand, optionally, about 3 mg to about 19 mg of a sustained releasedelivery system. In another embodiment, the second layer includes about45 mg nalbuphine or a pharmaceutically acceptable salt of nalbuphine andabout 110 mg to about 150 mg of a sustained release delivery system; andthe first layer includes from about 10 mg to about 20 mg nalbuphine or apharmaceutically acceptable salt of nalbuphine. In this embodiment, thefirst layer does not include a sustained release delivery system. Insome embodiments, the sustained release delivery system includes about12% to 42% by weight locust bean gum, about 8% to about 28% by weightxanthan gum, about 20% to about 70% by weight mannitol and about 5% toabout 20% by weight calcium sulfate dihydrate.

In one aspect, the invention provides an oral unit dosage form includingnalbuphine or a pharmaceutically acceptable salt thereof. The oraldosage form provides an analgesic effect over a period of at least about12 hours. In some embodiments, the oral dosage form provides a bloodserum level of nalbuphine characterized by one or more peaks followed bya plateau region. In some embodiments, the oral dosage form ischaracterized in that 75-100% of the nalbuphine is released after about12 hours as determined using USP Apparatus III at 15 dpm in a pH 6.8buffer at 37° C.

In one aspect, the invention provides an oral unit dosage form of amedicament including a uniform dosage of nalbuphine; and a sustainedrelease delivery system. The oral unit dosage form is characterized inthat the dosage form erodes so that nalbuphine is released in one ormore peaks followed by a plateau region.

The invention also provides methods for treating pain in patients byadministering an effective amount of any of the compositions of theinvention. The pain may be moderate to severe. In some embodiments, thepain is acute pain, chronic pain, nociceptive pain, neuropathic pain,visceral pain, or idiopathic pain.

The invention also provides methods for making such compositions.

These and other aspects of the invention are described in detail herein.

DESCRIPTION OF THE DRAWINGS

A more complete appreciation of the invention and many of its advantageswill be understood by reference to the description of the invention whenconsidered in connection with the following drawings, which arepresented for the purpose of illustration only and are not intended tobe limiting and in which:

FIG. 1 is a graphical representation of the log of the mean nalbuphineplasma concentration versus time for numerous nalbuphine compositionsdescribed herein.

DETAILED DESCRIPTION OF THE INVENTION

The invention provides oral sustained release formulations of nalbuphineincluding an analgesically effective amount of nalbuphine or apharmaceutically acceptable salt thereof. The oral sustained releaseformulations of the invention provide a controlled release of the drugover a longer period than observed for injectable or immediate releaseoral formulations (e.g., at least about 8-12 hours). Thus, by reducingthe frequency of dosing, the invention provides the potential forenhanced patient convenience. The lower dosing frequency also has thepotential to provide reduced side effects because the patient may beexposed to lower peak concentrations of drug over time.

The invention provides compositions including nalbuphine or apharmaceutically acceptable salt thereof and a sustained releasedelivery system. The sustained release delivery system includes (i) atleast one hydrophilic compound, at least one cross-linking agent, and atleast one pharmaceutical diluent; (ii) at least one hydrophiliccompound, at least one cross-linking agent, at least one pharmaceuticaldiluent, and at least one cationic cross-linking agent different fromthe first cross-linking agent; or (iii) at least one hydrophiliccompound, at least one cationic cross-linking compound, and at least onepharmaceutical diluent.

The nalbuphine may be homogeneously dispersed in the sustained releasedelivery system. In some embodiments, the nalbuphine or pharmaceuticallyacceptable salt thereof is present in the composition in an amount ofabout 1 mg to about 200 mg; about 1 mg to about 150 mg; about 1 mg toabout 125 mg; or about 1 mg to about 100 mg. In some embodiments, thenalbuphine or pharmaceutically acceptable salt thereof is present in thecomposition in an amount of about 5 mg to about 80 mg; about 10 mg toabout 70 mg; about 15 mg to about 60 mg; about 40 mg to about 80 mg;about 50 mg to about 70 mg; or about 45 mg to about 60 mg. In oneembodiment, the nalbuphine or pharmaceutically acceptable salt thereofis present in the composition in an amount of about 20 mg, about 40 mg,about 60 mg, about 75 mg, about 80 mg, about 100 mg, about 120 mg, about140 mg, about 150 mg, about 160 mg, about 175 mg, about 180 mg or about200 mg. In another embodiment, the nalbuphine or pharmaceuticallyacceptable salt thereof is present in the composition in an amount ofabout 45 mg.

In some embodiments, the sustained release delivery system is present inthe composition in an amount from about 10 mg to about 420 mg; fromabout 25 mg to about 225 mg; from about 21 mg to about 198 mg; or fromabout 80 mg to about 200 mg; from about 80 mg to about 220 mg; fromabout 90 mg to about 210 mg; from about 100 mg to about 200 mg; fromabout 110 mg to about 190 mg; from about 120 mg to about 180 mg; fromabout 130 mg to about 170 mg; from about 140 mg to about 160 mg; fromabout 30 mg to about 60 mg; from about 60 mg to about 180 mg; from about30 mg to about 180 mg, from about 75 mg to about 150 mg, from about 80mg to about 160 mg, from about 90 mg to about 150 mg, from about 100 mgto about 140 mg, from about 110 mg to about 130 mg, from about 100 mg toabout 300 mg, from about 200 mg to about 300 mg or from about 200 mg toabout 250 mg. In one embodiment, the sustained release delivery systemis present in the composition in an amount from about 75 mg to about 150mg. In some embodiments, the sustained release delivery system ispresent in the composition in an amount of about 30 mg, about 60 mg,about 75 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about112 mg, about 115 mg, about 117 mg, about 120 mg, about 125 mg, about130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about210 mg, about 220 mg, about 225 mg, about 230 mg, about 240 mg, about250 mg, about 260 mg, about 270 mg, about 280 mg, about 300 mg, about320 mg, about 340 mg, about 360 mg, about 380 mg, about 400 mg or about420 mg. In another embodiment, the sustained release delivery system ispresent in the composition in an amount of about 112 mg. “Nalbuphine”includes nalbuphine, metabolites thereof, derivatives thereof, and/orpharmaceutically acceptable salts thereof. Metabolites of nalbuphineinclude, for example the glucuronide conjugate metabolite andmetabolites resulting from methylation, oxidation/dehydrogenation,hydroxylation, double hydroxylation, triple hydroxylation, oxidativemethylation, glucoside conjugation, glucuronide conjugation, andhydroxyl-glucuronide conjugation of nalbuphine. Isomers include theC-6β-epimer of nalbuphine (Mallinckrodt, Nalbuphine hydrochlorideTechnical Package August 2003).

In the compositions of the invention, the ratio of nalbuphine orpharmaceutically acceptable salt thereof to the sustained releasedelivery system is generally from about 4:1 to about 1:25. In someembodiments, the ratio of nalbuphine or pharmaceutically acceptable saltthereof to the sustained release delivery system is generally from about2.5:1 to about 1:4. In some embodiments, the ratio of nalbuphine orpharmaceutically acceptable salt thereof to the sustained releasedelivery system is generally from about 5:1 to about 1:5, about 4:1 toabout 1:4, about 3:1 to about 1:3, about 2:1 to about 1:2, about 1:1 toabout 1:5, about 1:1 to about 1:4, about 1:1 to about 1:3, about 1:1 toabout 1.2, and about 1:2 to about 1:3. In some embodiments, the ratio ofnalbuphine or pharmaceutically acceptable salt thereof to the sustainedrelease delivery system is about 1:1, about 1:2, about 1:2.5, about 1:3,about 1:4, or about 1:5.

In one embodiment, the at least one hydrophilic compound is present inthe sustained release delivery system in an amount of about 5% to about80% by weight; the at least one cross-linking agent is present in thesustained release delivery system in an amount of about 0.5% to about80% by weight; and the at least one pharmaceutical diluent is present inthe sustained release delivery system in an amount of about 20% to about80% by weight. In another embodiment, the at least one hydrophiliccompound is present in the sustained release delivery system in anamount of about 8% to about 31 % by weight; the at least onecross-linking agent is present in the sustained release delivery systemin an amount of about 12% to about 47% by weight; and the at least onepharmaceutical diluent is present in the sustained release deliverysystem in an amount of about 20% to about 78% by weight. In anotherembodiment, the at least one hydrophilic compound is present in thesustained release delivery system in an amount of about 10% to about 20%by weight; the at least one cross-linking agent is present in thesustained release delivery system in an amount of about 15% to about 25%by weight; and the at least one pharmaceutical diluent is present in thesustained release delivery system in an amount of about 50% to about 85%by weight. In some embodiments, the at least one hydrophilic compound ispresent in the sustained release delivery system in an amount of about8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%,about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about22%, about 24%, about 26%, about 28%, or about 30% by weight; the atleast one cross-linking agent is present in the sustained releasedelivery system in an amount of about 10%, about 11%, about 12%, about13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%,about 20%, about 22%, about 24%, about 26%, about 28%, about 30%, about32%, about 33%, about 34%, or about 35% by weight; and the at least onepharmaceutical diluent is present in the sustained release deliverysystem in an amount of about 40%, about 45%, about 50%, about 55%, about60%, about 65%, about 70%, about 80%, or about 85% by weight. In someembodiments, the at least one hydrophilic compound is present in thesustained release delivery system in an amount of about 10%, about 11%,about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about18%, about 19%, or about 20% by weight; the at least one cross-linkingagent is present in the sustained release delivery system in an amountof about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, orabout 22% by weight; and the at least one pharmaceutical diluent ispresent in the sustained release delivery system in an amount of about55%, about 60%, about 65%, about 70%, about 80%, or about 85% by weight.In one embodiment, the at least one hydrophilic compound is present inthe sustained release delivery system in an amount of about 8%, about12%, or about 20% by weight; the at least one cross-linking agent ispresent in the sustained release delivery system in an amount of about12%, about 18%, or about 30% by weight; and the at least onepharmaceutical diluent is present in the sustained release deliverysystem in an amount of about 40%, about 60%, or about 70% by weight.

In one embodiment, nalbuphine is in the form of any pharmaceuticallyacceptable salt known in the art. Exemplary pharmaceutically acceptablesalts include without limitation hydrochloric, sulfuric, nitric,phosphoric, hydrobromic, maleric, malic, ascorbic, citric, tartaric,pamoic, lauric, stearic, palmitic, oleic, myristic, lauryl sulfuric,napthalinesulfonic, linoleic, linolenic acid, and the like. Oneembodiment includes the hydrochloride salt of nalbuphine.

The sustained release delivery system includes at least one hydrophiliccompound. The hydrophilic compound preferably forms a gel matrix thatreleases the nalbuphine or the pharmaceutically acceptable salt thereofat a sustained rate upon exposure to liquids. The rate of release of thenalbuphine or the pharmaceutically acceptable salt thereof from the gelmatrix depends on the drug's partition coefficient between thecomponents of the gel matrix and the aqueous phase within thegastrointestinal tract. In the compositions of the invention, the weightratio of nalbuphine to hydrophilic compound is generally in the range ofabout 10:1 to about 1:10, about 9:1 to about 1:9, about 8:1 to about1:8, about 7:1 to about 1:7, about 6:1 to about 1:6, about 5:1 to about1:5, about 4:1 to about 1:4, about 3:1 to about 1:3, and about 2:1 toabout 1:2. In some embodiments, the weight ratio of nalbuphine tohydrophilic compound is in the range of about 10:1 to about 1:1, about10:1 to about 2:1, about 9:1 to about 1:1, about 8:1 to about 1:1, about7:1 to about 1:1, about 6:1 to about 1:1, about 5:1 to about 1:1, about4:1 to about 1:1, about 3:1 to about 1: 1, and about 2:1 to about 1:1.In some embodiments, the weight ratio of nalbuphine to hydrophiliccompound is in the range of about 6:1 to about 1:1, about 5:1 to about2:1, about 4:1 to about 3:1, about 4:1 to about 2:1, and about 5:1 toabout 2:1. In some embodiments, the weight ratio of nalbuphine tohydrophilic compound is about 5:1, about 4.5:1, about 4.4:1, about 4:1,about 3.5:1, about 3.3:1, about 3:1, about 2.5:1, and about 2:1.

The sustained release delivery system generally includes the hydrophiliccompound in an amount of about 5% to about 80% by weight. In someembodiments, the sustained release delivery system generally includesthe hydrophilic compound in an amount of about 5% to about 30%, about 8%to about 31%, about 10% to about 20%, about 20% to about 60%, or about40% to about 60% by weight. In one embodiment, the sustained releasedelivery system includes the hydrophilic compound in an amount of about8% to about 31% by weight. In one embodiment, the sustained releasedelivery system includes the hydrophilic compound in an amount of about10% to about 20% by weight. In some embodiments, the sustained releasedelivery system includes the hydrophilic compound in an amount of about10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%,about 17%, about 18%, about 19%, or about 20% by weight. In oneembodiment, the sustained release delivery system includes thehydrophilic compound in an amount of about 12% by weight. In oneembodiment, the sustained release delivery system includes thehydrophilic compound in an amount of about 8% by weight. In oneembodiment, the sustained release delivery system includes thehydrophilic compound in an amount of about 20% by weight. In oneembodiment, the sustained release delivery system includes thehydrophilic compound in an amount of about 28% by weight.

The hydrophilic compound is any compound known in the art to behydrophilic. Exemplary hydrophilic compounds include without limitationgums, cellulose ethers, acrylic resins, polyvinyl pyrrolidone,protein-derived compounds, and mixtures thereof. Exemplary gums includewithout limitation heteropolysaccharide gums and homopolysaccharidegums, such as xanthan, tragacanth, pectins, acacia, karaya, alginates,agar, guar, hydroxypropyl guar, carrageenan, locust bean gums, andgellan gums. Exemplary cellulose ethers include without limitationhydroxyalkyl celluloses and carboxyalkyl celluloses. In someembodiments, cellulose ethers include hydroxyethyl celluloses,hydroxypropyl celluloses, hydroxypropylmethyl-celluloses, carboxymethylcelluloses, and mixtures thereof. Exemplary acrylic resins includewithout limitation polymers and copolymers of acrylic acid, methacrylicacid, methyl acrylate and methyl methacrylate. In some embodiments, thehydrophilic compound is a gum. In other embodiments, the hydrophiliccompound is a heteropolysaccharide gum. In further embodiments, thehydrophilic compound is a xanthan gum or derivative thereof. Derivativesof xanthan gum include without limitation, for example, deacylatedxanthan gum, the carboxymethyl esters of xanthan gum, and the propyleneglycol esters of xanthan gum.

In another aspect, the sustained release delivery system furtherincludes at least one cross-linking agent. In one embodiment, thecross-linking agent is a compound that is capable of cross-linking thehydrophilic compound to form a gel matrix in the presence of liquids. Asused herein, “liquids” includes, for example, gastrointestinal fluidsand aqueous solutions, such as those used for in vitro dissolutiontesting. The sustained release delivery system generally includes thecross-linking agent in an amount of about 0.5% to about 80% by weight.In one embodiment, the sustained release delivery system generallyincludes the cross-linking agent in an amount of about 12% to about 47%by weight. In another embodiment, the sustained release delivery systemgenerally includes the cross-linking agent in an amount of about 20% toabout 30% by weight. In one embodiment, the sustained release deliverysystem generally includes the cross-linking agent in an amount of about15% to about 25% by weight. In some embodiments, the at least onecross-linking agent is present in the sustained release delivery systemin an amount of about 15%, about 16%, about 17%, about 18%, about 19%,about 20%, about 21%, about 22%, about 23%, about 24%, or about 25% byweight. In one embodiment, the sustained release delivery systemincludes the cross-linking agent in an amount of about 18% by weight. Inone embodiment, the sustained release delivery system includes thecross-linking agent in an amount of about 12% by weight. In oneembodiment, the sustained release delivery system includes thecross-linking agent in an amount of about 30% by weight. In oneembodiment, the sustained release delivery system includes thecross-linking agent in an amount of about 42% by weight.

Exemplary cross-linking agents include homopolysaccharides. Exemplaryhomopolysaccharides include without limitation galactomannan gums, suchas guar gum, hydroxypropyl guar gum, and locust bean gum. In someembodiments, the cross-linking agent is a locust bean gum or a guar gum.In other embodiments, the cross-linking agent is an alginic acidderivative or hydrocolloid.

In some embodiments, when the sustained release delivery system includesat least one hydrophilic compound and at least one cross-linking agent,the weight ratio of hydrophilic compound to cross-linking agent is fromabout 1:9 to about 9:1, about 1:8 to about 8:1, about 1:7 to about 7:1,about 1:6 to about 6:1, about 1:5 to about 5:1, about 1:4 to about 4:1,about 1:3 to about 3:1, or about 1:2 to about 2:1. In some embodiments,the weight ratio of hydrophilic compound to cross-linking agent is about1:5, about 1:4.5, about 1:4, about 1:3.5, about 1:3, about 1:2.5, about1:2, about 1:1.5, and about 1:1.

When the sustained release delivery system includes at least onehydrophilic compound and at least one cross-linking agent, the weightratio of the nalbuphine or pharmaceutically acceptable salt thereof tothe sum of the at least one hydrophilic compound and the at least onecross-linking agent is from about 10:1 to about 1:10, from about 9:1 toabout 1:9, from about 8:1 to about 1:8, from about 7:1 to about 1:7,from about 6:1 to about 1:6, from about 5:1 to about 1:5, from about 4:1to about 1:4, from about 3:1 to about 1:3, or from about 2:1 to about1:2. In some embodiments, the weight ratio of the nalbuphine orpharmaceutically acceptable salt thereof to the sum of the at least onehydrophilic compound and the at least one cross-linking agent is fromabout 4:1 to about 1:1, from about 4:1 to about 1:1.5, from about 3:1 toabout 1:1, or from about 2:1 to about 1:1. In one embodiment, the ratioof the nalbuphine or pharmaceutically acceptable salt thereof to the sumof the at least one hydrophilic compound and the at least onecross-linking agent is about 5:1, about 4:1 (i. e., 1:0.25), about3.5:1, about 3:1, about 2.5:1, about 2:1 (i.e., 1:0.5), about 1.9:1,about 1.8:1, about 1.7:1, about 1.6:1, about 1.5:1, about 1.4:1, about1.3:1, about 1.2:1, about 1.1:1, about 1:1, about 1:1.5, about 1:2,about 1:3 (i.e., 1:0.75), about 1:4, and about 1:5.

The sustained release delivery system further includes one or morepharmaceutical diluents known in the art. Exemplary pharmaceuticaldiluents include without limitation monosaccharides, disaccharides,polyhydric alcohols and mixtures thereof. In some embodiments,pharmaceutical diluents include, for example, starch, mannitol, lactose,dextrose, sucrose, microcrystalline cellulose, sorbitol, xylitol,fructose, and mixtures thereof. In some embodiments, the pharmaceuticaldiluent is water-soluble. Nonlimiting examples of water-solublepharmaceutical diluents include lactose, dextrose, sucrose, or mixturesthereof. The weight ratio of pharmaceutical diluent to hydrophiliccompound is generally from about 1:9 to about 9:1, from about 1:8 toabout 8:1, from about 1:7 to about 7:1, from about 1:6 to about 6:1,from about 1:5 to about 5:1, from about 1:4 to about 4:1, from about 1:3to about 3:1, or from about 1:2 to about 2:1. In some embodiments, theweight ratio of pharmaceutical diluent to hydrophilic compound isgenerally from about 9:1 to about 1:1.5. In some embodiments, the weightratio of pharmaceutical diluent to hydrophilic compound is about 9:1,about 8.75:1, about 8.5:1, about 8.25:1, about 8:1, about 7.5:1, about7:1, about 6.5:1, about 6:1, about 5.5:1, about 5:1, about 4.5:1, about4:1, about 3.5:1, about 3:1, about 2.5:1, about 2:1, about 1.5:1, orabout 1:1.

The sustained release delivery system generally includes one or morepharmaceutical diluents in an amount of about 20% to about 80%, about30% to about 70%, about 40% to about 70%, or about 40% to about 60%. Inone embodiment, the sustained release delivery system includes one ormore pharmaceutical diluents in an amount of about 20% to about 70% byweight. In one embodiment, the sustained release delivery systemincludes one or more pharmaceutical diluents in an amount of about 50%to about 85% by weight. In some embodiments, the sustained releasedelivery system includes one or more pharmaceutical diluents in anamount of about 55%, about 60%, about 65%, about 70%, about 80%, orabout 85% by weight. In one embodiment, the sustained release deliverysystem includes one or more pharmaceutical diluents in an amount ofabout 20% by weight. In one embodiment, the sustained release deliverysystem includes one or more phannaceutical diluents in an amount ofabout 30% by weight. In one embodiment, the sustained release deliverysystem includes one or more pharmaceutical diluents in an amount ofabout 40% by weight. In one embodiment, the sustained release deliverysystem includes one or more pharmaceutical diluents in an amount ofabout 50% by weight. In one embodiment, the sustained release deliverysystem includes one or more pharmaceutical diluents in an amount ofabout 60% by weight. In one embodiment, the sustained release deliverysystem includes one or more pharmaceutical diluents in an amount ofabout 70% by weight.

In a further aspect, the sustained release delivery system of theinvention includes one or more cationic cross-linking compounds. In someembodiments, the one or more cationic cross-linking compounds are usedinstead of the cross-linking agent. In some embodiments, the one or morecationic cross-linking compounds are used in addition to thecross-linking agent. In one embodiment, the one or more cationiccross-linking compounds are used in an amount sufficient to cross-linkthe hydrophilic compound to form a gel matrix in the presence ofliquids. In some embodiments, the one or more cationic cross-linkingcompounds are present in the sustained release delivery system in anamount of about 0.5% to about 30%, about 0.5% to about 25%, about 0.5%to about 20%, about 0.5% to about 15%, about 0.5% to about 10%, or about0.5% to about 5% by weight. In some embodiments, the one or morecationic cross-linking compounds are present in the sustained releasedelivery system in an amount of about 5% to about 20%, about 5% to about15%, about 6% to about 14%, about 7% to about 13%, about 8% to about12%, or about 9% to about 11% by weight. In some embodiments, the one ormore cationic cross-linking compounds are present in the sustainedrelease delivery system in an amount of about 5%, about 6%, about 7%,about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about14%, or about 15% by weight. In one embodiment, the cationiccross-linking compound is present in the sustained release deliverysystem in an amount of about 10% by weight.

Exemplary cationic cross-linking compounds include without limitationmonovalent metal cations, multivalent metal cations, and inorganicsalts, including alkali metal and/or alkaline earth metal sulfates,chlorides, borates, bromides, citrates, acetates, lactates, and mixturesthereof. For example, the cationic cross-linking compound includewithout limitation one or more of calcium sulfate, sodium chloride,potassium sulfate, sodium carbonate, lithium chloride, tripotassiumphosphate, sodium borate, potassium bromide, potassium fluoride, sodiumbicarbonate, calcium chloride, magnesium chloride, sodium citrate,sodium acetate, calcium lactate, magnesium sulfate, sodium fluoride, ormixtures thereof.

When the sustained release delivery system includes at least onehydrophilic compound and at least one cationic cross-linking compound,the weight ratio of hydrophilic compound to cationic cross-linkingcompound ranges from about 1:9 to about 9:1, from about 1:8 to about8:1, from about 1:7 to about 7:1, from about 1:6 to about 6:1, fromabout 1:5 to about 5:1, from about 1:4 to about 4:1, from about 1:3 toabout 3:1, or from about 1:2 to about 2:1. In one embodiment, the weightratio of hydrophilic compound to cationic cross-linking compound rangesfrom about 1:3 to about 3:1. In some embodiments, the weight ratio ofhydrophilic compound to cationic cross-linking compound is about 3:1,about 2.75:1, about 2.5:1, about 2.25:1, about 2:1, about 1.8:1, about1.6:1, about 1.4:1, about 1.2:1, about 1:1, about 1:1.25, about 1:1.5,or about 1:2. In one embodiment, the weight ratio of hydrophiliccompound to cationic cross-linking compound is about 1:1.25. In oneembodiment, the weight ratio of hydrophilic compound to cationiccross-linking compound is about 1.2:1. In one embodiment, the weightratio of hydrophilic compound to cationic cross-linking compound isabout 2:1. In one embodiment, the weight ratio of hydrophilic compoundto cationic cross-linking compound is about 2.8:1.

In one embodiment, the at least one hydrophilic compound is present inthe sustained release delivery system in an amount of about 5% to about80% by weight; the at least one cationic cross-linking agent is presentin the sustained release delivery system in an amount of about 0.5% toabout 30% by weight; and the at least one pharmaceutical diluent ispresent in the sustained release delivery system in an amount of about20% to about 80% by weight. In another embodiment, the at least onehydrophilic compound is present in the sustained release delivery systemin an amount of about 8% to about 30% by weight; the at least onecationic cross-linking agent is present in the sustained releasedelivery system in an amount of about 10% by weight; and the at leastone pharmaceutical diluent is present in the sustained release deliverysystem in an amount of about 20% to about 70% by weight. In anotherembodiment, the at least one hydrophilic compound is present in thesustained release delivery system in an amount of about 5% to about 30%by weight; the at least one cationic cross-linking agent is present inthe sustained release delivery system in an amount of about 5% to about20% by weight; and the at least one pharmaceutical diluent is present inthe sustained release delivery system in an amount of about 20% to about85% by weight. In another embodiment, the at least one hydrophiliccompound is present in the sustained release delivery system in anamount of about 10% to about 20% by weight; the at least one cationiccross-linking agent is present in the sustained release delivery systemin an amount of about 5% to about 15% by weight; and the at least onepharmaceutical diluent is present in the sustained release deliverysystem in an amount of about 50% to about 85% by weight. In someembodiments, the at least one hydrophilic compound is present in thesustained release delivery system in an amount of about 8%, about 9%,about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about16%, about 17%, about 18%, about 19%, about 20%, about 22%, about 24%,about 26%, about 28%, or about 30% by weight; the at least one cationiccross-linking agent is present in the sustained release delivery systemin an amount of about 5%, about 6%, about 7%, about 8%, about 9%, about10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%,about 17%, about 18%, about 19%, or about 20%, by weight; and the atleast one pharmaceutical diluent is present in the sustained releasedelivery system in an amount of about 40%, about 45%, about 50%, about55%, about 60%, about 65%, about 70%, about 80%, or about 85% by weight.In one embodiment, the at least one hydrophilic compound is present inthe sustained release delivery system in an amount of about 10%, about11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%,about 18%, about 19%, or about 20% by weight; the at least one cationiccross-linking agent is present in the sustained release delivery systemin an amount of about 5%, about 6%, about 7%, about 8%, about 9%, about10%, about 11%, about 12%, about 13%, about 14%, about 15%, by weight;and the at least one pharmaceutical diluent is present in the sustainedrelease delivery system in an amount of about 55%, about 60%, about 65%,about 70%, about 80%, or about 85% by weight. In one embodiment, the atleast one hydrophilic compound is present in the sustained releasedelivery system in an amount of about 8%, about 12%, or about 20% byweight; the at least one cationic cross-linking agent is present in thesustained release delivery system in an amount of about 10%, about 12%,or about 14% by weight; and the at least one pharmaceutical diluent ispresent in the sustained release delivery system in an amount of about40%, about 60%, or about 70% by weight.

In one embodiment, the sustained release delivery system includes about0.5% to about 80% locust bean gum, about 5% to about 80% xanthan gum,about 20% to about 80% mannitol and about 0.5% to 80% calcium sulfatedihydrate. In one embodiment, the sustained release delivery systemincludes about 12% to about 47% locust bean gum, about 8% to about 31%xanthan gum, about 20% to about 78% mannitol and about 0.5% to 25%calcium sulfate dihydrate. In one embodiment, the sustained releasedelivery system includes about 15% to about 25% locust bean gum, about10% to about 20% xanthan gum, about 50% to about 85% mannitol and about5% to 15% calcium sulfate dihydrate. In one embodiment, the sustainedrelease delivery system includes about 18% locust bean gum, about 12%xanthan gum, about 60% mannitol and about 10% calcium sulfate dihydrate.In one embodiment, the sustained release delivery system includes about12% locust bean gum, about 8% xanthan gum, about 70% mannitol and about10% calcium sulfate dihydrate. In one embodiment, the sustained releasedelivery system includes about 20% locust bean gum, about 30% xanthangum, about 40% mannitol and about 10% calcium sulfate dihydrate. In oneembodiment, the sustained release delivery system includes about 30%locust bean gum, about 20% xanthan gum, about 40% mannitol and about 10%calcium sulfate dihydrate. In one embodiment, the sustained releasedelivery system includes about 42% locust bean gum, about 28% xanthangum, about 20% mannitol and about 10% calcium sulfate dihydrate.

Two properties of the components of this system (e.g., the at least onehydrophilic compound and the at least one cross-linking agent; or the atleast one hydrophilic compound and at least one cationic cross-linkingcompound) that forms a gel matrix upon exposure to liquids are fasthydration of the compounds/agents and the ability to form a gel matrixhaving a high gel strength. These two properties, which are needed toachieve a slow release gel matrix, are maximized in the invention by theparticular combination of compounds (e.g., the at least one hydrophiliccompound and the at least one cross-linking agent; or the at least onehydrophilic compound and the at least one cationic cross-linkingcompound). For example, hydrophilic compounds (e.g., xanthan gum) haveexcellent water-wicking properties that provide fast hydration. Thecombination of hydrophilic compounds with materials that are capable ofcross-linking the rigid helical ordered structure of the hydrophiliccompound (e.g., cross-linking agents and/or cationic cross-linkingcompounds) thereby acts synergistically to provide a higher thanexpected viscosity (i.e., high gel strength) of the gel matrix.

In some embodiments, the compositions described herein are furtheradmixed with one or more wetting agents (e.g., polyethoxylated castoroil, polyethoxylated hydrogenated castor oil, polyethoxylated fatty acidfrom castor oil, polyethoxylated fatty acid from hydrogenated castoroil) one or more lubricants (e.g., magnesium stearate, sodium stearylfumarate, and the like), one or more buffering agents, one or morecolorants, and/or other conventional ingredients.

In some embodiments, the compositions described herein further include asecond hydrophilic compound. In some embodiments, the second hydrophiliccompound is a cellulose ether. In some embodiments, the secondhydrophilic compound is a hydroxyalkyl cellulose or a carboxyalkylcellulose. In some embodiments, the second hydrophilic compound is ahydroxyethyl cellulose, a hydroxypropyl cellulose, ahydroxypropylmethyl-cellulose, a carboxy methylcellulose, or a mixturethereof. In some embodiments, the second hydrophilic is an ethylcellulose or wax (e.g., including without limitation cetyl alcohol,stearyl alcohol, white wax, or camoba wax). The second hydrophiliccompound is present in the formulation in an amount ranging from about5% to about 45%, about 5% to about 25%, about 10% to about 20%, or 12%to about 18% by weight. In some embodiments, the second hydrophiliccompound is present in the formulation in an amount of about 5%, about6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%,about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about30%, about 35%, about 40%, or about 45%.

In some embodiments, the weight ratio of the second hydrophilic compoundto the nalbuphine or pharmaceutically acceptable salt ranges from about5:1 to about 1:5, about 4:1 to about 1:4, about 3:1 to about 1:3, about2:1 to about 1:2, about 1:1 to about 1:3, or about 1:1 to about 1:2. Insome embodiments, the weight ratio of the second hydrophilic compound tothe nalbuphine or pharmaceutically acceptable salt is about 5:1, about4:1, about 3:1, about 2:1, about 1:1, about 1:2, about 1:3, about 1:4,or about 1:5.

In some embodiments, the weight ratio of the second hydrophilic compoundto the sustained release delivery system ranges from about 10:1 to about1:10, about 8:1 to about 1:8, about 6:1 to about 1:6, about 4:1 to about1:4, about 2:1 to about 1:3, about 1:1 to about 1:10, about 1:1 to about1:6, or about 1:2 to about 1:6. In some embodiments, the weight ratio ofthe second hydrophilic compound to the sustained release delivery systemis about 10:1, about 8:1, about 6:1, about 4:1, about 2:1, about 1:1,about 1:1.5, about 1:2, about 1:2.5, about 1:3, about 1:4, about 1:5,about 1:6, about 1:7, about 1:8, about 1:9 or about 1:10.

In some embodiments, the invention provides oral sustained release soliddosage formulations including from about 1 mg to 200 mg nalbuphinehydrochloride and about 10 mg to about 420 mg of a sustained releasedelivery system. In these embodiments, the sustained release deliverysystem includes about 12% to about 42% locust bean gum; about 8.0% toabout 28% xanthan gum; about 20% to about 70% mannitol; and about 5% toabout 20% calcium sulfate dihydrate. In some embodiments, the inventionprovides oral sustained release solid dosage formulations including fromabout 5 mg to about 80 mg nalbuphine hydrochloride and about 80 mg toabout 360 mg of a sustained release delivery system. In someembodiments, the invention provides oral sustained release solid dosageformulations including from about 50 mg to about 150 mg nalbuphinehydrochloride and about 100 mg to about 300 mg of a sustained releasedelivery system.

In some embodiments, the invention provides oral sustained release soliddosage formulations including about 60 mg nalbuphine hydrochloride andfrom about 25 mg to about 225 mg of a sustained release delivery system.In these embodiments, the sustained release delivery system includesabout 18% locust bean gum; about 12% xanthan gum; about 60% mannitol;and about 10% calcium sulfate dihydrate. In some embodiments, theinvention provides oral sustained release solid dosage formulationsincluding from about 5 mg to about 80 mg nalbuphine hydrochloride andabout 80 mg to about 360 mg of a sustained release delivery system.

In some embodiments, the invention provides oral sustained release soliddosage formulations including about 45 to about 60 mg nalbuphinehydrochloride and from about 100 mg to about 200 mg of a sustainedrelease delivery system. In these embodiments, the sustained releasedelivery system includes about 15% to about 25% locust bean gum; about10% to about 20% xanthan gum; about 50% to about 85% mannitol; and about5% to about 15% calcium sulfate dihydrate.

The sustained release formulations of nalbuphine are orallyadministrable solid dosage formulations. Nonlimiting examples of oralsolid dosage formulations include tablets, capsules including aplurality of granules, sublingual tablets, powders, granules, syrups,and buccal dosage forms. In some embodiments, tablets have an entericcoating or a hydrophilic coating.

The sustained release delivery system is prepared by dry granulation orwet granulation, before the nalbuphine or pharmaceutically acceptablesalt thereof is added, although the components may be held together byan agglomeration technique to produce an acceptable product. In the wetgranulation technique, the components (e.g., hydrophilic compounds,cross-linking agents, pharmaceutical diluents, cationic cross-linkingcompounds, hydrophobic polymers, etc.) are mixed together and thenmoistened with one or more liquids (e.g., water, propylene glycol,glycerol, alcohol) to produce a moistened mass that is subsequentlydried. The dried mass is then milled with conventional equipment intogranules of the sustained release delivery system. Thereafter, thesustained release delivery system is mixed in the desired amounts withthe nalbuphine or the pharmaceutically acceptable salt thereof and,optionally, one or more wetting agents, one or more lubricants, one ormore buffering agents, one or more coloring agents, one or more secondhydrophilic compounds, or other conventional ingredients, to produce agranulated composition. The sustained release delivery system and thenalbuphine may be blended with, for example, a high shear mixer. Thenalbuphine is preferably finely and homogeneously dispersed in thesustained release delivery system. The granulated composition, in anamount sufficient to make a uniform batch of tablets, is subjected totableting in a conventional production scale tableting machine attypical compression pressures, i.e., about 2,000-16,000 psi. In someembodiments, the mixture should not be compressed to a point where thereis subsequent difficulty with hydration upon exposure to liquids.

In some embodiments, the nalbuphine formulation is prepared by drygranulation or wet granulation. The components of the sustained releasedelivery system are added, along with the nalbuphine or pharmaceuticallyacceptable salt thereof. Alternatively, all of the components may beheld together by an agglomeration technique to produce an acceptableproduct. In the wet granulation technique, nalbuphine orpharmaceutically salt thereof and the components (e.g., hydrophiliccompounds, cross-linking agents, pharmaceutical diluents, cationiccross-linking compounds, hydrophobic polymers, etc.) are mixed togetherand then moistened with one or more liquids (e.g., water, propyleneglycol, glycerol, alcohol) to produce a moistened mass that issubsequently dried. The dried mass is then milled with conventionalequipment into granules. Optionally, one or more wetting agents, one ormore lubricants, one or more buffering agents, one or more coloringagents, one or more second hydrophilic compounds, or other conventionalingredients, are also added to the granulation. The granulatedcomposition, in an amount sufficient to make a uniform batch of tablets,is subjected to tableting in a conventional production scale tabletingmachine at typical compression pressures, i.e., about 2,000-16,000 psi.In some embodiments, the mixture should not be compressed to a pointwhere there is subsequent difficulty with hydration upon exposure toliquids.

The average particle size of the granulated composition is from about 50μm to about 400 μm by weight. In some embodiments, the average particlesize by weight is from about 185 μm to about 265 μm. The average densityof the granulated composition is from about 0.3 g/mL to about 0.8 g/mL.In some embodiments, the average density is from about 0.5 g/mL to about0.7 g/mL. The tablets formed from the granulations are generally fromabout 4 Kp to about 22 kP hardness. The average flow of the granulationsis from about 25 to about 40 g/sec.

In one aspect, the invention provides a multilayer solid dosage form, inwhich the layers are formulated to release the nalbuphine hydrochlorideat different rates. For example, in one embodiment, the second layer isan extended release layer that includes nalbuphine or a pharmaceuticallyacceptable salt thereof and a sustained release delivery system designedto release the nalbuphine or the pharmaceutically acceptable saltthereof at a controlled rate so that therapeutically beneficial bloodlevels are maintained over an extended period of time (e.g., from about8 to about 12 hours). The first layer is an immediate release layer thatincludes a formulation of nalbuphine or a pharmaceutically acceptablesalt thereof designed to release the nalbuphine or the pharmaceuticallyacceptable salt thereof at a rate that is faster than the rate of thesecond layer to achieve a therapeutically beneficial blood level in animmediate period of time (e.g., from about 1 to about 2 hours). In someembodiments, the first layer includes a sustained release deliverysystem. In some embodiments, the first layer does not include asustained release delivery system.

In some embodiments, the weight ratio of the second layer to the firstlayer is about 10:1 to about 1:10, about 9:1 to about 1:9, about 8:1 toabout 1:8, about 7:1 to about 1:7, about 6:1 to about 1:6, about 5:1 toabout 1:5, about 4:1 to about 1:4, about 3:1 to about 1:3, about 2:1 toabout 1:2. In one embodiment, the weight ratio of the second layer tothe first layer is about 5:1 to about 1:5. In a further embodiment, theweight ratio of the second layer to the first layer is about 1:1 toabout 1:2. In some embodiments, the weight ratio of the second layer tothe first layer is about 1:1, about 1:1.2, about 1:1.4, about 1:1.6,about 1:1.8, or about 1:2. In one embodiment, the weight ratio of thesecond layer to the first layer is about 1:2. In one embodiment, theweight ratio of the second layer to the first layer is about 1:1.4. Insome embodiments, the weight ratio of the second layer to the firstlayer is about 3:1, about 2.5:1, about 2:1, about 1.5:1. In oneembodiment, the weight ratio of the second layer to the first layer isabout 2.5:1.

The sustained release delivery system of the multilayer dosage formincludes (i) at least one hydrophilic compound, at least onecross-linking agent, and at least one pharmaceutical diluent; (ii) atleast one hydrophilic compound, at least one cross-linking agent, atleast one pharmaceutical diluent, and at least one cationiccross-linking agent different from the first cross-linking agent; or(iii) at least one hydrophilic compound, at least one cationiccross-linking compound, and at least one pharmaceutical diluent. In someembodiments, when the first layer includes a sustained release deliverysystem, the sustained release delivery system of the first layerincludes the same components as the sustained release delivery system ofthe second layer (e.g., both the first and second layers are one ofembodiments (i)-(iii), listed above). In other embodiments, thesustained release delivery system of the first layer includes differentcomponents as the sustained release delivery system of the second layer(e.g., the first layer is embodiment (i), listed above, while the secondlayer is embodiment (iii), listed above). It is recognized that thesustained release delivery system of either layer can be one ofembodiments (i)-(iii) listed above. Moreover, it is recognized that insome embodiments, the first layer does not include a sustained releasedelivery system.

The sustained release delivery system is generally present in the secondlayer (i.e., extended release layer) in an amount ranging from about 10mg to about 420 mg. In some embodiments, the sustained release deliverysystem is present in the second layer in an amount ranging from about110 mg to about 200 mg. In some embodiments, the sustained releasedelivery system is present in the second layer in an amount ranging fromabout 110 mg to about 150 mg. In some embodiments, the sustained releasedelivery system is present in the second layer in an amount ranging fromabout 90 mg to about 150 mg. In some embodiments, the sustained releasedelivery system is present in the second layer in an amount of about 50mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg,about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg,about 160 mg, about 170 mg, about 180 mg, about 190 mg, or about 200 mg.In one embodiment, the sustained release delivery system is present inthe second layer in an amount of about 123 mg. In one embodiment, thesustained release delivery system is present in the second layer in anamount of about 101 mg. In one embodiment, the sustained releasedelivery system is present in the second layer in an amount of about 92mg. In another embodiment, the sustained release delivery system ispresent in the second layer in an amount of about 112.5 mg. In oneembodiment, the sustained release delivery system is present in thesecond layer in an amount of about 135 mg. In one embodiment, thesustained release delivery system is present in the second layer in anamount of about 150 mg.

Nalbuphine or a pharmaceutically acceptable salt thereof is generallypresent in the second layer in an amount ranging from about 30 mg toabout 60 mg. In some embodiments, nalbuphine or a pharmaceuticallyacceptable salt thereof is present in the second layer in an amountranging from about 45 mg to about 60 mg. In one embodiment, nalbuphineor a pharmaceutically acceptable salt thereof is present in the secondlayer in an amount of about 45 mg. In one embodiment, nalbuphine or apharmaceutically acceptable salt thereof is present in the second layerin an amount of about 60 mg.

In some embodiments, the weight ratio of nalbuphine or pharmaceuticallyacceptable salt thereof to the sustained release delivery system in thesecond layer is about 10:1 to about 1:10, about 9:1 to about 1:9, about8:1 to about 1:8, about 7:1 to about 1:7, about 6:1 to about 1:6, about5:1 to about 1:5, about 4:1 to about 1:4, about 3:1 to about 1:3, orabout 2:1 to about 1:2. In one embodiment, the weight ratio ofnalbuphine or pharmaceutically acceptable salt thereof to the sustainedrelease delivery system in the second layer is about 1:2 to about 1:4.In one embodiment, the weight ratio of nalbuphine or pharmaceuticallyacceptable salt thereof to the sustained release delivery system in thesecond layer is about 1:1 to about 1:5. In some embodiments, the weightratio of nalbuphine or pharmaceutically acceptable salt thereof to thesustained release delivery system in the second layer is about 1: 1,about 1:1.2, about 1:1.4, about 1:1.6, about 1:1.8, about 1:2, about1:2.5, about 1:3, or about 1:3.5. In one embodiment, the weight ratio ofnalbuphine or pharmaceutically acceptable salt thereof to the sustainedrelease delivery system in the second layer is about 1:2.5. In anotherembodiment, the weight ratio of nalbuphine or pharmaceuticallyacceptable salt thereof to the sustained release delivery system in thesecond layer is about 1:3.3. In a further embodiment, the weight ratioof nalbuphine or pharmaceutically acceptable salt thereof to thesustained release delivery system in the second layer is about 1:3. Inyet another embodiment, the ratio of nalbuphine or pharmaceuticallyacceptable salt thereof to the sustained release delivery system in thesecond layer is about 1:2.

When the sustained release delivery system is present in the first layer(i.e., immediate release layer), it is generally present in an amountranging from about 0 mg to about 50 mg. In some embodiments, thesustained release delivery system is present in the first layer in anamount ranging from about 5 mg to about 25 mg or from about 5 mg toabout 15 mg. In one embodiment, the sustained release delivery system ispresent in the first layer in an amount of about 3 mg to about 9 mg. Inone embodiment, the sustained release delivery system is present in thefirst layer in an amount of about 4 mg to about 6 mg. In someembodiments, the sustained release delivery system is present in thefirst layer in an amount of about 2 mg, about 4 mg, about 6 mg, about 8mg, about 10 mg, about 12 mg, about 14 mg, about 15 mg, about 16 mg,about 18 mg, about 20 mg about 25 mg, about 30 mg, about 35 mg, about 40mg, about 45 mg or about 50 mg. In one embodiment, the sustained releasedelivery system is present in the first layer in an amount of about 6mg.

Nalbuphine or a pharmaceutically acceptable salt thereof is generallypresent in the first layer (i.e., immediate release layer) in an amountranging from about 5 mg to about 50 mg. In some embodiments, nalbuphineor a pharmaceutically acceptable salt thereof is present in the firstlayer in an amount ranging from about 5 mg to about 25 mg or from about10 mg to about 20 mg. In some embodiments, the nalbuphine or apharmaceutically acceptable salt thereof is present in the first layerin an amount of about 5 mg, about 10 mg, about 11 mg, about 12 mg, about13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg,about 19 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about40 mg, about 45 mg or about 50 mg. In one embodiment, nalbuphine or apharmaceutically acceptable salt thereof is present in the first layerin an amount of about 15 mg.

In some embodiments, when the first layer includes a sustained releasedelivery system, the ratio of nalbuphine or pharmaceutically acceptablesalt thereof to the sustained release delivery system in the first layeris about 10:1 to about 1:10, about 9:1 to about 1:9, about 8:1 to about1:8, about 7:1 to about 1:7, about 6:1 to about 1:6, about 5:1 to about1:5, about 4:1 to about 1:4, about 3:1 to about 1:3, about 2:1 to about1:2. In one embodiment, the ratio of nalbuphine or pharmaceuticallyacceptable salt thereof to the sustained release delivery system in thefirst layer is about 2:1 to about 4:1. In some embodiments, the ratio ofnalbuphine or pharmaceutically acceptable salt thereof to the sustainedrelease delivery system in the first layer is about 5:1, about 4.5:1,about 4:1, about 3.5:1, about 3:1, about 2.5:1, about 2:1, about 1.5:1,or about 1:1. In one embodiment, the ratio of nalbuphine orpharmaceutically acceptable salt thereof to the sustained releasedelivery system in the first layer is about 2.5:1. In anotherembodiment, the ratio of nalbuphine or pharmaceutically acceptable saltthereof to the sustained release delivery system in the first layer isabout 3:1.

In some embodiments, the multilayer dosage form further includes apharmaceutical disintegrant. The disintegrant promotes the dissolutionand absorption of nalbuphine or pharmaceutically acceptable salt thereoffrom the immediate release layer. Nonlimiting examples of pharmaceuticaldisintegrants include croscarmellose sodium, starch glycolate,crospovidone, and unmodified starch. In one embodiment, the disintegrantis in the first layer (i.e., the immediate release layer), of the dosageform. The disintegrant is generally present in the layer in an amount ofabout 1.5 mg to about 4.5 mg. In one embodiment, the disintegrant ispresent in an amount of about 3 mg. In one embodiment, the disintegrantis present in the layer in an amount of about 2-10% by weight. In oneembodiment, the disintegrant is present in the layer in an amount ofabout 5% by weight. When the layer contains a sustained release deliverysystem, the weight ratio of the sustained release delivery system to thedisintegrant is in a range of about 5:1 to about 1:5. In someembodiments, the ratio of the sustained release delivery system to thedisintegrant is in a range of about 1:1 to about 3:1. In otherembodiments, the ratio of the sustained release delivery system to thedisintegrant is in a range of about 2:1.

In some embodiments, the multilayer tablets of the invention areprepared by first preparing the immediate release layer and extendedrelease layer blends separately. The extended release layer is preparedas described above. The wet granulation of the extended release layer isthen dried and milled to an appropriate size. Magnesium stearate isadded and mixed with the milled granulation. The immediate release layerof the invention is prepared by first mixing the nalbuphine or thepharmaceutically acceptable salt thereof with one or more diluents(e.g., microcrystalline cellulose). This mix is then optionally mixedwith one or more disintegrants. The blend is mixed with magnesiumstearate. Finally, the immediate release layer blend and the extendedrelease layer blend are compressed into multi-layer (e.g., bi-layer)tablets.

The invention provides methods for treating pain by administering aneffective amount of a sustained release formulation of nalbuphine to apatient in need thereof. An effective amount is an amount sufficient toeliminate all pain or to alleviate the pain (i.e., reduce the paincompared to the pain present prior to administration of the nalbuphinesustained release formulation). “Sustained release” or “extendedrelease” means that the nalbuphine or pharmaceutically acceptable saltthereof is released from the formulation at a controlled rate so thattherapeutically beneficial blood levels (but below toxic levels) of thenalbuphine or pharmaceutically acceptable salt thereof are maintainedover an extended period of time. Alternatively, “sustained release” or“extended release” means that the desired pharmacologic effect ismaintained over an extended period of time. Clinical trials of theformulations described herein have surprisingly found that the durationof analgesic effect is longer than expected. The half-life ofexperimental orally administered nalbuphine formulations (i.e.,immediate release formulations) has been reported to be relativelyshort, only about 5-7 hours. Moreover, the published literature suggeststhat the duration of effect for experimental formulations of immediaterelease nalbuphine was only about 4 hours. Based on these data, it wasexpected that a sustained release formulation would provide a durationof analgesic effect for approximately 6-8 hours, i.e., allowing for 2-3times daily dosing. In the clinical trials described herein, however, itwas surprisingly discovered that the nalbuphine sustained releaseformulations had an analgesic effect of longer than 8 hours. In somecases, the duration of analgesic effect was at least about 12 hours,thus providing the possibility of fewer dosing administrations, whichwas heretofore not thought to be possible.

Without wishing to be bound by a particular theory, the longer thanexpected duration of analgesic effect is thought to be due to theenterohepatic recirculation of nalbuphine. Nalbuphine forms a glucuronicacid or other type of conjugated metabolite in vivo through enzymaticreaction with an enzyme system such as UDP-glucuronyl transferase. Onceformed, the conjugated nalbuphine product is thought to be transportedinto the gastrointestinal tract via biliary secretion whereby the drugconjugate is cleaved liberating nalbuphine which can be reabsorbed fromthe intestine. It is thought that nalbuphine formulations that have beentested in the past that had a large bolus of nalbuphine in an immediaterelease formulation (e.g., greater than about 25 mg) may have saturatedthe enzymatic conjugation system, allowing other digestive or hepaticenzymes (e.g., the cytochrome P450 enzymes) to metabolize the nalbuphineinto non-therapeutically active metabolites of nalbuphine and resultingin low oral availability for nalbuphine itself. The sustained releaseformulation may improve bioavailability and, thus the duration ofanalgesic effect, by more slowly releasing nalbuphine into the in vivosystem and allowing more drug to be conjugated and therefore availablefor recirculation and later reabsorption from the intestine.

The sustained release formulations of nalbuphine are administered in anamount sufficient to alleviate pain for a period ranging from about 6hours to about 18 hours. In some embodiments, the formulations areadministered in an amount sufficient to alleviate pain up to about 6hours to about 8 hours. In other embodiments, the formulations areadministered in an amount sufficient to alleviate pain up to about 8hours to about 12 hours. In some embodiments, the formulations areadministered in an amount sufficient to alleviate pain up to about 12hours. In some embodiments, the formulations are administered in anamount sufficient to alleviate pain for at least about 12 hours, 15hours, or 18 hours. The nalbuphine sustained release oral solid dosageformulations of the invention are administered one to four times a day.In some embodiments, the formulations are administered one to threetimes a day. In some embodiments, the formulations are administeredthree times a day. In other embodiments, the formulations areadministered two times a day. In still other embodiments, theformulations are administered one time a day. In some embodiments, thepain is minor to moderate to severe. In other embodiments, the pain ismoderate to severe. In some embodiments, the nalbuphine formulationsdisclosed herein are appropriate for treating a patient experiencingchronic pain (i.e., where pain is experienced over a long term, such aslasting months, years or life-long). Exemplary conditions that the painis associated with include without limitation back pain (e.g., low-backpain), cancer, autoimmune diseases, infections, surgical traumas,accidental traumas or osteoarthritis. In some embodiments, thenalbuphine formulations disclosed herein are useful for treatingnociceptive pain (e.g., chronic lower back pain, pain associated withcancer, HIV infection, rheumatoid arthritis, osteoarthritis, trauma(e.g., sprains, bone fractures, burns, bumps, bruises), inflammation,myofascial pain, or post-operative pain), neuropathic pain (e.g., painassociated with diabetic neuropathy, postherpetic neuralgia, CLBT,cancer, HIV infection or AIDS, nerve injury, the “dynias” (e.g.,vulvodynia), phantom limb pain, root avulsions, painful traumaticmononeuropathy, painful polyneuropathy, trigeminal neuralgia,post-stroke pain, multiple sclerosis-associated pain, spinal cordinjury, neuropathies-associated pain such as in idiopathic orpost-traumatic neuropathy and mononeuritis, carpal tunnel-associatedneuropathic pain, spinal cord injury-associated pain, complex regionalpain syndrome, fibromyalgia-associated neuropathic pain, lumbar andcervical pain, reflex sympathic dystrophy, and neuropathic painassociated with drug therapy), visceral pain (e.g., pain caused, forexample, by a burn, a bruise, an abrasion, a laceration, a broken bone,a torn ligament, a tom tendon, a torn muscle, a viral infection, abacterial infection, a protozoal infection, a fungal infection, contactdermatitis, inflammation, or cancer), and idiopathic pain (e.g., painassociated with fibromyalgia and regional myofascial pain syndromes,arthritis, chronic fatigue syndrome, irritable bowel syndrome,interstitial cystitis, and carpal tunnel syndrome) and other chronic anddebilitating condition-associated pain syndromes. In some embodiments,the patient is an animal. In other embodiments, the patient is a mammal.In further embodiments, the patient is a human.

In one aspect, the uses of the sustained release formulations ofnalbuphine further include the use of one or more therapeutic agentsselected from the group consisting of opioids, non-opioid analgesics,non-steroidal anti-inflammatory drugs (NSAIDs), COX-2 inhibitors,acetaminophen, diclofenac, diflunisal, etodolac, flurbiprofen,ibuprofen, indomethacin, ketoprofen, ketorolac, naburnetone, naproxen,oxaprozin, piroxicam, sulindac, tolmetin, celecoxib, rofecoxib,valdecoxib, codeine, morphine, methadone, oxymorphone, hydromorphone,oxycodone, hydrocodone, levorphanol, fentanyl, meperidine, timerol,tramadol, naloxone, Stadol, Talwin, buprenorphine, butorphanol,naltrexone and aspirin.

In certain embodiments, upon oral ingestion of the nalbuphine sustainedrelease formulation and contact of the formulation with gastrointestinalfluids, the sustained release formulation swells and gels to form ahydrophilic gel matrix from which the nalbuphine is released. Theswelling of the gel matrix causes a reduction in the bulk density of theformulation and provides the buoyancy necessary to allow the gel matrixto float on the stomach contents to provide a slow delivery of thenalbuphine. The hydrophilic matrix, the size of which is dependent uponthe size of the original formulation, can swell considerably and becomeobstructed near the opening of the pylorus. Because the nalbuphine isdispersed throughout the formulation (and consequently throughout thegel matrix), a constant amount of nalbuphine is released per unit timein vivo by dispersion or erosion of the outer portions of thehydrophilic gel matrix. The process continues, with the gel matrixremaining buoyant in the stomach, until substantially all of thenalbuphine is released.

In certain embodiments, the chemistry of certain of the components ofthe formulation, such as the hydrophilic compound (e.g., xanthan gum),is such that the components are considered to be self-buffering agentswhich are substantially insensitive to the solubility of the nalbuphineand the pH changes along the length of the gastrointestinal tract.Moreover, the chemistry of the components is believed to be similar tocertain known muco-adhesive substances, such as polycarbophil.Muco-adhesive properties are desirable for buccal delivery systems.Thus, the sustained release formulation can loosely interact with themucin in the gastrointestinal tract and thereby provide another mode bywhich a constant rate of delivery of the nalbuphine is achieved.

The two phenomenon discussed above (buoyancy and muco-adhesiveproperties) are mechanisms by which the sustained release formulationsof the invention can interact with the mucin and fluids of thegastrointestinal tract and provide a constant rate of delivery of thenalbuphine.

When measured by USP Procedure Drug Release General Chapter <711>Dissolution, (incorporated by reference herein in its entirety), thesustained release formulations of the invention generally exhibit an invitro dissolution of about 15% to about 50% by weight nalbuphine after 1hour, about 45% to about 80% by weight nalbuphine after 4 hours, or atleast about 80% by weight nalbuphine after 10 hours. In someembodiments, the in vitro and in vivo release characteristics of thesustained release formulations of the invention are modified usingmixtures of one or more different water insoluble and/or water solublecompounds, using different plasticizers, varying the thickness of thesustained release film, including providing release-modifying compoundsin the coating, and/or by providing passageways through the coating. Insome embodiments, the dissolution rate is determined using apparatus USPType III/250 mL at pH 6.8, 37° C. and 15 dpm. In some embodiments, thedissolution rate is determined using apparatus USP Type III/250 mLperformed in pH change (0-1 hours pH 1.2, after hour 1 pH 4.5, afterhour 2 pH 6.8) at 37° C. and 15 dpm.

In some embodiments, the sustained release formulation has an in vitrodissolution of about 50% to about 100% by weight nalbuphine after about6 hours. In some embodiments, the sustained release formulation has anin vitro dissolution of about 75% to about 100% by weight nalbuphineafter about 6 hours. In other embodiments, the sustained releaseformulation has an in vitro dissolution of about 75% to about 100% byweight nalbuphine from about 6 hours to about 8 hours. In furtherembodiments, the sustained release formulation has an in vitrodissolution of about 80% to about 100% by weight nalbuphine after about12 hours. In still other embodiments, the sustained release formulationhas an in vitro dissolution of about 80% to about 100% by weightnalbuphine from about 12 hours to about 24 hours. In some embodiments,the sustained release formulation has an in vitro dissolution of about80% to about 100% after about 8 hours to about 12 hours. In yet otherembodiments, the sustained release formulation has an in vitrodissolution of about 15% to about 75% by weight nalbuphine after about 1hour. In still further embodiments, the sustained release formulationhas an in vitro dissolution of about 50% by weight nalbuphine afterabout 1 hour. In some embodiments, the sustained release formulation hasan in vitro dissolution of about 50% by weight nalbuphine after about 1hour and about 75% to about 100% by weight nalbuphine from about 6 hoursto about 8 hours. In some embodiments, the sustained release formulationhas an in vitro dissolution of about 50% by weight nalbuphine afterabout 1 hour and about 75% to about 100% by weight nalbuphine from about8 hours to about 12 hours. In some embodiments, the sustained releaseformulation has an in vitro dissolution of about 50% by weightnalbuphine after about 1 hour and about 75% to about 100% by weightnalbuphine from about 12 hours to about 24 hours. In some embodiments,the sustained release formulation has an in vitro dissolution of about50% by weight nalbuphine after about 1 hour and about 80% to about 100%by weight nalbuphine after about 12 hours.

Where the tablet is a multilayer dosage form having a first extendedrelease layer and a second, immediate release, layer, the sustainedrelease formulation has an in vitro dissolution of about 25% to about75% by weight nalbuphine after about 1 hour. In some embodiments, themultilayer dosage form has an in vitro dissolution of about 25% byweight nalbuphine after about 1 hour. In some embodiments, themultilayer dosage form has an in vitro dissolution of about 50% byweight nalbuphine after about 1 hour. In some embodiments, themultilayer dosage form has an in vitro dissolution of about 75% to about100% nalbuphine after about 6-8 hours. In some embodiments, themultilayer dosage form has an in vitro dissolution of about 75% to about100% nalbuphine after about 8-12 hours. In some embodiments, themultilayer dosage form has an in vitro dissolution of about 75% to about100% nalbuphine after about 12-24 hours. In some embodiments, themultilayer dosage form has an in vitro dissolution of about 75% to about100% nalbuphine after about 12 hours.

When administered orally to patients the sustained release formulationsdescribed herein exhibit the following in vivo characteristics: (a) apeak plasma level of nalbuphine occurs within about 2 to about 6 hoursafter administration; (b) onset of nalbuphine analgesic effect fromabout 30 minutes of dosing to within about 6 hours of dosing; (c)duration of the nalbuphine analgesic effect is about 2 to about 24hours; and (c) the relative nalbuphine bioavailability is about 0.5 toabout 1.5 compared to an orally administered aqueous solution ofnalbuphine. The time of onset for an analgesic effect can depend on atleast on dosing and the type of pain relief sought. In some embodiments,the duration of the nalbuphine analgesic effect is at least about 8hours. In some embodiments, the duration of the nalbuphine analgesiceffect is at least about 9 hours. In some embodiments, the duration ofthe nalbuphine analgesic effect is at least about 10 hours. In someembodiments, the duration of the nalbuphine analgesic effect is at leastabout 11 hours. In some embodiments, the duration of the nalbuphineanalgesic effect is at least about 12 hours. In some embodiments, theduration of nalbuphine analgesic effect is about 6, hours, 8 hours, 10hours, 12 hours, 15 hours, or 18 hours. In some embodiments, therelative nalbuphine bioavailability is about 1.25 compared to an orallyadministered aqueous solution of nalbuphine. In some embodiments, therelative nalbuphine bioavailability is about 1.35 compared to an orallyadministered aqueous solution of nalbuphine.

In some embodiments, the sustained release nalbuphine formulationsdescribed herein invention provides an oral unit dosage form includingnalbuphine or a pharmaceutically acceptable salt thereof. The oraldosage form provides an analgesic effect over a period of at least about6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours,about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15hours, about 16 hours, about 17 hours, or about 18 hours. In someembodiments, the oral dosage form provides an analgesic effect over aperiod of about 6-18 hours, about 8-16 hours, about 8-12 hours, or about8-10 hours. The oral dosage form provides an analgesic effect over aperiod of about 6 hours, about 7 hours, about 8 hours, about 9 hours,about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14hours, about 15 hours, about 16 hours, about 17 hours, or about 18hours.

In some embodiments, the oral dosage form provides a blood serum levelof nalbuphine characterized by one or more peaks followed by a plateauregion. The plateau region is characterized as having a relativelyconsistent blood serum level of nalbuphine (e.g., the blood serum levelof nalbuphine does consistently increase or decrease from time point totime point). In some embodiments, the plateau region is characterized ashaving a consistent average blood serum level of nalbuphine. The plateauregion is contrasted with the region following the plateau region, inwhich the blood serum level of nalbuphine generally decreases from onetime point to the next. In some embodiments, the plateau region has aduration of at least about 1 hour, about 2 hours, about 3 hours, about 4hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about9 hours, about 10 hours, about 11 hours or about 12 hours. In someembodiments, the plateau region has a duration from about 1 hour toabout 12 hours, from about 2 hours to about 10 hours, from about 2 hoursto about 8 hours, from about 2 hours to about 7 hours or from about 4hours to about 10 hours, from about 4 hours to about 8 hours, or fromabout 4 hours to about 6 hours. In some embodiments, the blood serumlevel of nalbuphine at each time point in the plateau region ranges fromabout 75% to about 125% of the mean blood serum level in the plateauregion. In some embodiments, the blood serum level of nalbuphine at eachtime point in the plateau region ranges from about 80% to about 120% ofthe mean blood serum level in the plateau region. In some embodiments,the blood serum level of nalbuphine at each time point in the plateauregion ranges from about 85% to about 115% of the mean blood serum levelin the plateau region. In some embodiments, the blood serum level ofnalbuphine at each time point in the plateau region ranges from about90% to about 110% of the mean blood serum level in the plateau region.In some embodiments, the minimum blood serum level of nalbuphineobserved during the plateau region is not more than about 25% below themean blood serum level for all time points in the plateau region. Insome embodiments, the minimum blood serum level of nalbuphine observedduring the plateau region is not more than about 20% below the meanblood serum level in the plateau region. In some embodiments, theminimum blood serum level of nalbuphine observed during the plateauregion is not more than about 15% below the mean blood serum level inthe plateau region. In some embodiments, the minimum blood serum levelof nalbuphine observed during the plateau region ranges from about 75%to about 100% of the mean blood serum level in the plateau region. Insome embodiments, the minimum blood serum level of nalbuphine observedduring the plateau region ranges from about 80% to about 100% of themean blood serum level in the plateau region. In some embodiments, theminimum blood serum level of nalbuphine observed during the plateauregion ranges from about 85% to about 100% of the mean blood serum levelin the plateau region. In some embodiments, the minimum blood serumlevel of nalbuphine observed during the plateau region ranges from about80% to about 95% of the mean blood serum level in the plateau region.

While the compositions of the invention may be administered as the soleactive pharmaceutical compound in the methods described herein, they canalso be used in combination with one or more compounds which are knownto be therapeutically effective against pain.

The invention further provides methods of treating pain comprisingadministering to a mammal in need thereof the sustained releasenalbuphine formulations described herein in an amount effective to treatpain. In some embodiments, methods of treating pain include treatingchronic pain or acute pain. In some embodiments, methods of treatingpain include nociceptive pain, europathis pain, visceral pain oridiopathic pain.

The sustained release nalbuphine formulations described herein are alsouseful in the manufacture of medicaments for treating pain in a mammal.In some embodiments, the formulations are useful in the manufacture ofmedicaments for treating pain in a mammal.

The invention also provides pharmaceutical kits including one or morecontainers filled with one or more of the compositions of the invention.The kits may further include other pharmaceutical compounds known in theart to be therapeutically effective against pain, and instructions foruse, in particular instructions for using the compositions for thetreatment of pain, including chronic pain. In one embodiment, theinvention provides a package or a kit including the sustained releasecompositions described herein and instructions for treating pain

EXAMPLES

The following examples are for purposes of illustration only and are notintended to limit the scope of the appended claims.

Examples 1 to 3

Three sustained release delivery systems were prepared by dry blendingxanthan gum, locust bean gum, calcium sulfate dihydrate, and mannitol ina high speed mixed/granulator for 3 minutes. While runningchoppers/impellers, water was sprayed to the dry blended mixture, andgranulated for another 6 minutes. Then the granulation process wasstopped and the mixer/granulation bowl was scraped. While runningchoppers/impellers, the granulation was mixed for one more minute. Afterthe granulation was checked for consistency, while runningchoppers/impellers additional water was added to the granulation andgranulated for additional 3.5 minutes. The granulation was then dried toLOD (loss on drying) of less than about 4% by weight. The granulationwas then milled using screen #1521-0033. The relative quantities of theingredients are listed in Table 1. TABLE 1 Sustained Release DeliverySystem Example 1 Example 2 Example 3 Excipient % % % Xanthan Gum, NF 8.012.0 20.0 Locust Bean Gum, FCC 12.0 18.0 30.0 Mannitol, USP 70.0 60.040.0 Calcium Sulfate Dihydrate, NF 10.0 10.0 10.0 Sterile Water ForInjection, USP¹ Total 100.0 100.0 100.0¹Sterile Water for Injection, USP is removed during processing

Examples 4 to 7

A series of tablets containing different amounts of gum were preparedusing the sustained release delivery system of Example 3. The quantitiesof ingredients per tablet are listed in Table 2. TABLE 2 Ex. 4 Ex. 5 Ex.6 Ex. 7 Component mg mg mg mg Nalbuphine HCl, USP  60  60  60  60Sustained release  60¹ 120¹ 180¹  90¹ delivery system Magnesiumstearate, NF  0.5  1.8  1.2  0.75 Total weight 120.5 181.8 241.2 150.75Active:Gum 1:0.5 1:1 1:1.5 1:0.75 Tooling Size  0.2812″  0.2812″ 0.3125″  0.2812″ Hardness (Kp)  1.2  8.8  8.9  7.2¹Sustained release system of Example 3

The tablets were prepared by mixing nalbuphine with the sustainedrelease delivery system in a mixer. The magnesium stearate was passedthrough a #30 mesh screen sieve and then mixed with the dry blendcontaining nalbuphine and the sustained release delivery system. Thislubricated blend was compressed using the tooling as specified in Table2 to make tablets of the total weight indicated.

The tablets of Examples 4-7 were tested for in vitro % release rateaccording to USP Procedure Drug Release General Chapter <711>Dissolution, using apparatus USP Type III/250 ml. The test was performedat pH 6.8, 37° C./15 dpm (dips per minute) in 100 mM ammonium phosphatebuffer. The results are shown in Table 3. TABLE 3 Dissolution timeExample 4 Example 5 Example 6 Example 7 (hours) pH 6.8 pH 6.8 pH 6.8 pH6.8 0 0 0 0 0 1 29.3 23.8 19.5 25.0 2 41.8 35.1 29.4 35.9 4 59.2 51.745.0 53.0 6 72.9 65.6 56.4 67.1 8 84.2 77.8 65.3 79.6 12  98.1 92.9 81.093.9 Remnant 4.3 5.9 16.3 6.0 % Recovery 102.4 98.8 97.3 99.9

Examples 8 to 10

A series of tablets containing different amounts of gum and differentsustained release delivery systems were prepared using the sustainedrelease delivery systems of Examples 1 and 2. The quantities ofingredients per tablet are listed in Table 4. TABLE 4 Ex. 8 Ex. 9 Ex. 10Component mg mg mg Nalbuphine HCl, USP  60  60  60 Sustained releasedelivery system 225² 150³ 100³ Magnesium stearate  1.43  1.1  0.8 Totalweight 286.4 211.1 160.8 Active:Gum 1:0.75 1:0.75 1:0.5 Tooling Size 0.3125″  0.3125″  0.2812″ Hardness (Kp)  20  17  20²Sustained release delivery system of Example 1³Sustained release delivery system of Example 2

The tablets were prepared by first mixing nalbuphine with the sustainedrelease delivery system in a mixer for Example 8 and in a high sheargranulator for Example 9 and 10. For Examples 9 and 10, the blend wasthen granulated with water until consistent granulation was achieved,followed by drying in a fluidized bed dryer for 30 minutes at 70° C. Thedried granules were then passed through a Fitzmill at 2500 rpm using1521-0050 screen. The magnesium stearate was passed through a #30 meshscreen sieve, and then mixed with the milled granules for Examples 9 and10 and with the dry blend for Example 8 for 5 minutes. The lubricatedblend was compressed using the tooling as specified in Table 4 to maketablets of the total weight indicated.

The tablets of Examples 8-10 were tested for in vitro % release rateaccording to USP Procedure Drug Release General Chapter <711>Dissolution, using apparatus USP Type III/250 ml. The test was performedin pH change, at 37° C./15 dpm. The pH change was as follows: pH 1.2 forthe first hour, pH 4.5 for the second hour, and pH 6.8 after the secondhour and through the duration of the test. The results are shown inTable 5. TABLE 5 Dissolution time Example 8 Example 9 Example 10 (hours)pH change pH change pH change 0 0.0 0 0 1 19.4 18.8 22.5 2 36.4 39.745.3 4 59.0 66.3 73.2 6 72.5 82.6 89 8 79.4 89.8 95.9 12  82.1 92.3100.1 Remnant 0.1 0.1 0.8 % Recovery 82.2 92.4 100.9

Examples 11 to 16

To determine the effect of the amount of gum in combination withmicrocrystalline cellulose (Emococel 90M), six batches of tablets wereprepared using the sustained release delivery system of Example 3. Therange of Active: Gum ratios used in Examples 11-16 varied between 1:0.25and 1:0.5. Compositions of the tablets are shown in Table6. TABLE 6 Ex.11 Ex. 12 Ex. 13 Ex. 14 Ex. 15 Ex. 16 Ingredient mg/tab mg/tab mg/tabmg/tab mg/tab mg/tab Sustained release  30⁴  60⁴  60⁴  30⁴  60⁴  60⁴delivery system Nalbuphine HCl 60 60 60 60 60 60 Microcrystalline 30 3060 60 120  — Cellulose Magnesium stearate   0.6   0.8   0.9   0.8   1.2  0.6 Total Weight (mg)  120.6  150.8  180.9  150.8  241.2  120.6Active:Gum 1:0.25 1:0.5 1:0.5 1:0.25 1:0.5 1:0.5 Tooling Size    0.2500″     0.2812″     0.2812″     0.2812″     0.3125″     0.2500″Hardness (Kp)   10.2 10 12 13 22   13.2⁴Sustained release delivery system of Example 3

The tablets of Examples 11-15 were prepared by first sifting magnesiumstearate through #30 mesh screen sieve. Then blend nalbuphine with thesustained release delivery system, and magnesium stearate in a blenderfor 5 minutes. The lubricated blend was compressed using the tooling asspecified in Table 6 to make tablets of the total weight indicated.

The tablets of Example 16 were prepared by mixing nalbuphine in a highshear granulator with the sustained release delivery system. The blendwas then granulated with water until consistent granulation wasachieved. The granulation is then dried in a fluidized bed dryer for 40minutes at 70° C. The dried granules were then passed through a Fitzmillat 2500 rpm using 1521-0050 screen. The magnesium stearate was passedthrough a #30 mesh screen sieve and then mixed with the milled granulesfor 5 minutes. The lubricated blend was compressed using the tooling asspecified in Table 6 to make tablets of the total weight indicated.

The tablets of Examples 11-16 were tested for in vitro % release rateaccording to USP Procedure Drug Release General Chapter <711>Dissolution, using apparatus USP Type III/250 ml. The test was performedin pH change, at 37° C./15 dpm, as described above for Examples 8-10.The results are shown in Table 7. TABLE 7 Dissolution time Ex. 11 Ex. 12Ex. 13 Ex. 14 Ex. 15 Ex. 16 (hours) pH change pH change pH change pHchange pH change pH change 0 0.0 0.0 0.0 0.0 0.0 0.0 1 93.2 59.4 94.593.4 92.1 17.1 2 94.4 73.0 96.0 94.8 93.4 39.7 4 94.5 84.5 96.0 94.893.5 64.4 6 94.5 87.4 96.0 94.8 93.5 74.6 8 94.5 88.7 96.0 94.8 93.581.5 12  94.5 90.2 96.0 94.8 93.5 93.1 Remnant 0.0 1.2 0.0 0.0 0.0 7.0 %Recovery 94.5 91.5 96.0 94.8 93.5 100.1

Examples 17 and 18

Two batches of bi-layer tablets were prepared using the sustainedrelease delivery system of Example 2 (Examples 17 and 18). In thebi-layer tablets, the first layer of the tablets was formulated toprovide relatively a slow sustained release; the second layer wasformulated to provide relatively fast (immediate) release. The in vitrodissolution profiles of the bi-layer tablets were compared to thedissolution profile of single layer tablets that were formulated toprovide a sustained release (Example 9). Compositions of the tablets areshown in Table 8. TABLE 8 Example 17 Example 18 Example 9 Ingredientmg/tab mg/tab mg/tab Extended release layer (ER) Sustained releasedelivery 112.5⁵ 112.9⁵ 150 system Nalbuphine HCl 45 45 60 Magnesiumstearate 0.8 0.8 1.1 ER weight 158.3 158.3 211.1 Immediate release layer(IR) Sustained release delivery 6.0⁵ N/A system Nalbuphine HCl 15.0 N/AMicrocrystalline Cellulose, 35.7 N/A NF(Emcocel 90 M) CroscarmelloseSodium, 3.0 N/A NF(Primellose ®) Magnesium stearate, NF 0.3 N/A IRWeight 60.0 N/A Total weight 218.3 218.3 211.1 Active:Gum 1:0.6 1:0.61:0.75 Tooling Size 0.2812″ 0.2812″ 0.3125″ Hardness N/A N/A 17⁵Sustained release delivery system of Example 2

For the extended release layer, the nalbuphine was mixed with thesustained release delivery system in a high shear granulator for 3minutes. The mixture was granulated with water until consistentgranulation was achieved, then the wet mass was dried in a fluidized beddryer for 20 minutes at 70° C. The dried granules were then passedthrough a Fitzmill at 2500 rpm using 1521-0050 screen. For the immediaterelease layer, the nalbuphine was blended with the sustained releasedelivery system, microcrystalline cellulose (Emcocel® 90M), andcroscarmellose sodium, NF (Primellose®) in a V-Blender for 10 minutes.The magnesium stearate was passed through a #30 mesh screen sieve. Themilled granules of the slow release layer was mixed with the sievedmagnesium stearate in a V-blender for 5 minutes and the dry blend of theimmediate release layer was mixed with the sieved magnesium stearate ina V-blender for 5 minutes, separately. This lubricated blend of theextended release layer and the immediate release layer were thencompressed into bi-layer tablets using the tooling specified in Table 8,to make the tablets of the total weight indicated.

The tablets of Examples 17-18 were tested for in vitro % release rateaccording to USP Procedure Drug Release USP General Chapter <711>Dissolution, using apparatus USP Type III/250 ml. The test was performedin pH change as described above for Examples 8-10, at 37° C./15 dpm, asdescribed above for Examples 8-10. The results are shown in Table 9. Forpurposes of comparing the dissolution profiles of the bi-layer tabletswith a single-layer tablet, the dissolution data for Example 9 is alsoshown in Table 9. TABLE 9 Dissolution time Ex. 17 Ex. 18 Ex. 9 (hours)pH change pH change pH change 0 0 0.0 0 1 44.5 42.6 18.8 2 62.8 62.739.7 4 83.1 84.3 66.3 6 92.3 92.3 82.6 8 94.0 93.7 89.8 12  94.1 93.992.3 Remnant 0.0 0.0 0.1 % Recovery 94.1 93.9 92.4

Examples 19 and 20

For a clinical study, one batch of bi-layer tablets and one batch ofsingle layer tablets were prepared using the sustained release deliverysystem of Example 2. The first layer of the tablets was formulated toprovide relatively a slow sustained release; the second layer wasformulated to provide relatively fast (immediate release). Compositionsof the tablets are shown in Table 10. TABLE 10 Component Amountmg/tablet (%) Ingredient Example 19(F-2) Example 20(F-1) Extendedrelease layer (ER) Sustained Release Excipient (30%) 112.5⁶ 150.0⁶Nalbuphine HCl 45.0 60.0 Magnesium stearate, NF 0.8 1.10 Sterile Waterfor Injection, USP* * * Mg/tablet weight (ER portion) 158.3 211.1Immediate release layer (IR) Nalbuphine HCl 15.0 MicrocrystallineCellulose, NF 41.7 Croscarmellose Sodium, NF 3.0 Magnesium stearate, NF0.3 Mg/tablet weight (IR portion) 60.0 Total Weight (mg/tablet) 218.3211.1 Type of tablet Bi-layer(ER/IR) Single layer (ER) Active to GumRatio 1:0.75 1:0.75 Tooling Size 0.3125 0.3125 Hardness ˜11 Kp ˜11 Kp*Sterile Water for Injection, USP is removed during process⁶Sustained release delivery system of Example 2

For the extended release layer of Example 19 and 20, the nalbuphine wasmixed with the sustained release delivery system in a high sheargranulator (6-liter Diosna-Pharma Mixer ⅙) for 5 minutes with theimpeller speed at 300 rpm and the chopper off. After the mixer stopped,the bowl was scraped and sample was taken for LOD. While the impellerand the chopper are running at 300 rpm, the mixture was granulated withwater for 2 minutes. After the mixer stopped, the bowl was scraped.While impeller speed is running at 500 rpm and the chopper speed at 300rpm, the granulation was continued by mixing for an additional 1 minute.At the end of mixing the bowel was scraped. While the impeller andchopper were running at 300 rpm, additional of water (about 50.0 g) wasadded and granulated for 2 minutes in Example 19 and for 1 minute inExample 20. To achieve consistent granules, the granulation was mixedfor additional 3 minutes in Example 19 and 1 minute in Example 20, whilethe impeller and chopper were running at 500 and 300 rpm, respectively.Then the wet mass was dried in a Uni-Glatt fluid bed dryer for 30minutes at 70° C. The dried granules were then passed through aFitzmill, knives forward, with the speed of 2200-2700 rpm using1521-0033 screen. The magnesium stearate was passed through a #30 meshscreen sieve. The milled granules of the extended release layer forExample 19 and 20 were mixed separately with the sieved magnesiumstearate in a V-blender with a 4-quart stainless steel shell for 5minutes.

For Example 20, the lubricated blend of the extended release layer wascompressed into single layer tablets with the Piccola tablet press usingthe tooling specified in Table 11, to make the tablets of the totalweight indicated.

In the immediate release layer portion of Example 19, the nalbuphine wasblended with the microcrystalline cellulose (Emcocel 90M) in a P-K BlendMaster V-Blender for 5 minutes. To the mixture, croscarmellose sodium,NF (Primellose®) was added and mixed for 5 minutes. The magnesiumstearate was passed through a #30 mesh screen sieve. The milled granulesof the extended release layer portion of Example 19 was mixed with thesieved magnesium stearate in a V-blender with a 4-quart stainless steelshell for 5 minutes and the dry blend of the immediate release layerportion was mixed with the sieved magnesium stearate in a V-blender witha 4-quart stainless steel shell for 5 minutes, separately. Thislubricated blend of the extended release layer portion and the immediaterelease layer portion were then compressed into bi-layer tablets withthe Piccola tablet press using the tooling specified in Table 10, tomake the tablets of the total weight indicated.

The tablets of Examples 19-20 were tested for in vitro % release rateaccording to USP Procedure Drug Release USP General Chapter <711>Dissolution, using apparatus USP Type III/250 ml. The test was performedin pH 6.8, at 37° C./15 dpm. The results are shown in Table 11. TABLE 11Dissolution Time (h) Example 19(F-2) Example 20(F-1) 0 0 0 1 47 26 3 6951 4 77 61 6 88 76 8 95 86 12  99 96 Remnant 0 2 Recovery 99 98

These data demonstrate that the dissolution rate from the bi-layer(ER/IR) formulation (Example 19(F-2)) was about 21% and 16% faster thanthe rate from the single layer (ER) formulation (Example 20(F-1)) at 1and 4 hours time point, respectively.

Clinical Study

A Phase I, open label, five treatment arm, single dose escalation studyunder fasting conditions was conducted and pharmacokinetic data wereobtained with the following formulations: a) the sustained deliverysystem-nalbuphine 60 mg bi-layer tablet (IR/ER) (Example 19 (F-2)), b)the sustained delivery system-nalbuphine 60 mg single layer tablet (ER)(Example 20(F-1)), c) two tablets of the 60 mg single layer tablet (ER,120 mg total dose), d) three tablets of the 60 mg single layer tablet(ER, 180 mg total dose) and e) a dose of nalbuphine immediate release 60mg oral solution (control). Eleven healthy volunteers were initiallyenrolled with six subjects completing all five treatments. Thepharmacokinetic data are summarized below both as arithmetic andgeometric mean results. The mean blood level (“plasma”) concentration ofnalbuphine for each time point is shown in Table 16. A logarithmic graphof the mean nalbuphine plasma concentration versus time for eachformulation is shown in FIG. 1. TABLE 12 Pharmacokinetic ParametersArithmetic Mean Values Cmax Tmax* AUC(0-t) AUC(0-inf) Formulation(ng/mL) (h) (ng * h/mL) (ng * h/mL)  60 mg (F-2) 8.58 1.5 75.95 83.87 60 mg (F-1) 7.17 3.5 78.73 90.70 120 mg (F-1) 12.87 6.0 154.39 170.75180 mg (F-1) 15.59 8.0 200.63 213.22  60 mg oral 13.75 1.0 61.85 68.50solution (IR)*Median Tmax values reported

TABLE 13 Relative Bioavailability (based on dose normalized arithmeticmean values) Cmax AUC (0-t) AUC (0-inf) ratio ratio ratio  60 mg(F-2)/ER 0.62 1.23 1.22  60 mg (F-1)/ER 0.52 1.27 1.32 120 mg (F-1)/ER0.47 1.25 1.25 180 mg (F-1)/ER 0.38 1.08 1.04

TABLE 14 Pharmacokinetic Parameters Geometric Mean Values Cmax AUC(0-t)AUC(0-inf) Formulation (ng/mL) (ng * h/mL) (ng * h/mL)  60 mg (F-2) 7.5868.72 77.85  60 mg (F-1) 6.28 69.95 85.65 120 mg (F-1) 12.24 140.61158.62 180 mg (F-1) 13.67 175.73 189.32  60 mg oral 12.48 56.29 63.14solution (IR)

TABLE 15 Relative Bioavailability (based on dose normalized geometricmean values) AUC (0-t) AUC (0-inf) Cmax ratio ratio ratio  60 mg(F-2)/IR 0.61 1.22 1.23  60 mg (F-1)/IR 0.50 1.24 1.36 120 mg (F-1)/IR0.49 1.25 1.26 180 mg (F-1)/IR 0.37 1.04 1.00

TABLE 16 Nalbuphine Blood Concentration Concentration (ng/mL) Time point60 mg 60 mg 120 mg 180 mg (hrs) 60 mg IR (F-1) (F-2) (F-1) (F1) 0 0 0 00 0 0.25 10.57 1.83 0.79 1.01 1.00 0.5 14.81 4.69 1.71 2.94 3.55 1 13.537.57 3.33 6.51 7.87 1.5 11.20 7.42 3.63 8.81 10.59 2 9.77 6.89 5.88 9.4111.40 3 6.58 6.18 4.96 9.04 11.90 4 4.65 5.36 4.77 8.20 10.71 6 3.295.31 6.18 10.45 14.01 8 1.76 4.00 4.76 8.55 10.59 12 1.67 2.83 3.32 6.779.20 16 1.01 1.87 2.24 4.27 5.14 20 0.76 1.13 1.51 2.96 3.27 24 0.680.84 1.11 2.02 2.46 36  NT* 0.57 0.54 0.94 0.98 48 NT NT NT NT 0.75*Not tested

In general, the F-1 (Example 20) and F-2 (Example 19) formulations hadhigher AUCs (0-t and 0-inf) and lower Cmax values (for both arithmeticand geometric mean values) compared to the immediate release oralsolution. These differences were moderate for AUCs (0-t and 0-inf) andmoderate to significant for Cmax and were based on dose-normalizedcomparisons of the F-1 and F-2 formulations with the immediate releaseoral solution. Minimal differences in AUCs (0-t and 0-inf) were seenbetween the F-1 and F-2 formulations at a comparative dose of 60 mg.

These data demonstrate that the oral bioavailability for the sustainedrelease nalbuphine formulations was greater than that of the immediaterelease control formulation. Specifically, the oral availability offormulation F-2 was 23% greater than that of the immediate release oralsolution, based on the geometric mean values for the area under theplasma concentration time curve. Similarly, the oral bioavailability ofFormulation F-1 was 36% greater than that of the immediate release oralsolution, based on the geometric mean values for the area under theplasma concentration time curve.

The Cmax values for the sustained release formulations wereapproximately 60% of the Cmax observed with the immediate release oralsolution. These data suggest that the potential for adverse events(i.e., side effects) could be decreased with the sustained releaseformulation compared to immediate release formulations.

Median Tmax values reported were 1.0, 1.5 and 3.5 hours for the oralsolution, F-2 and F-1 formulations, respectively. Longer Tmax valueswere observed for the 2 higher doses of the F-1 formulation (6.0 and 8.0hours for the 120 and 180 mg doses, respectively).

Dose linearity was observed for all three doses of the F-1 formulation(60, 120 and 180 mg), while the formulation was not dose proportionalover the entire dose range of 60 to 180 mg.

As shown in FIG. 1, the blood serum concentration of nalbuphine for theextended release formulations increases quickly to one or more peaksshortly following administration, followed by a plateau region. Theduration of the plateau period varies based on the dose strength andtype of formulation, but is generally in the range from about 1.5 hoursto about 10 hours. In contrast, the blood serum level for the immediaterelease formulation quickly maximizes, followed by an immediate decreasein nalbuphine concentration from time point to time point. Following theplateau period, there is a decrease in the nalbuphine blood plasmaconcentration from one time point to the next.

Example 21 Phase IIa Trial

A pilot Phase IIa trial pharmacokinetic-pharmacodynamic (PK-PD)investigation was designed to correlate the level of analgesia inpatients with the plasma level of nalbuphine in an extended release(sustained release) formulation (nalbuphine ER). This trial wasconducted to determine if there is an exposure-response relationship, aswell as to determine the duration of analgesia.

The nalbuphine ER formulation used in the study is represented by thatdescribed in Table 10, Example 19. The formulation was expected to haveplasma kinetics derived from both immediate release and controlledrelease components of the formulation. The formulation was a bilayeredtablet (Geminex®, Penwest Pharmaceuticals Co., Danbury Conn.) in whichone layer was a controlled release formulation using TIMERx® technology(Penwest Pharmaceuticals Co., Danbury, Conn.). The other layer wasformulated for immediate release of nalbuphine.

Patients in the trial underwent third molar extractions, a commonly usedclinical pain model for evaluating the acute effectiveness ofanalgesics. Under the protocol, patients who experienced at least ascore of four on the 0-to-10 NPRS pain scale following completion oftheir dental procedures received blinded study medication of 60 mgnalbuphine ER, 120 mg nalbuphine ER, or placebo as a single dose. Painrelief was then evaluated at pre-specified intervals over the 12-hourperiod following dosing. Blood samples were also collected atpre-specified intervals for 24 hours post-dose to determine of plasmaconcentrations of nalbuphine. Patients were allowed to take rescuemedication (ibuprofen, 800 mg) if needed. Pain assessments were carriedout for up to and including 12 hours in all patients, regardless of useof rescue medication. One hundred sixty-five patients were tested in thestudy.

A summary of the pharmacokinetic parameters from the Phase IIa trial areprovided below in Table 17 TABLE 17 Pharmacokinetic Parameters Cmax TmaxAUC Dose Group Statistic (ng/mL) (hr) (ng * hr/mL)  60 mg N 6.5 65 65Mean 8.1 4.5 75.2 SD 4.9 2.2 45.2 Median 6.6 6 65.3 120 mg N 66 66 66Mean 16.4 4.3 149.2 SD 10.6 2.7 77.0 Median 13.2 3 128.3

Results reported herein demonstrate that nalbuphine positively reducedthe pain intensity in a dose-dependent manner over 12 hours (Table 18).Differences from placebo began at 90 minutes post-dose for the higherstrength and at 6 hours for the lower strength, and were maintained atall time points over the remaining 12 hour dosing interval. Painintensity was assessed using an 11 -point (0 to 10) numeric pain ratingscale, ranging from “no pain” to “pain as bad as can be imagined”. TABLE18 Pain Intensity for Nalbuphine 60-mg and 120-mg Formulations Comparedto Placebo Timepoint (hrs Placebo 60 mg 120 mg postdose) Mean SD MedianMean SD Median p-value* Mean SD Median p-value* 0 6.1 1.6 6.0 6.2 1.46.0 6.0 1.5 6.0 (baseline)   0.25 5.8 1.7 6.0 6.2 1.5 6.0 0.2964 6.0 1.56.0 0.5265   0.50 5.9 2.0 6.0 6.1 1.8 6.0 0.7864 5.7 1.9 6.0 0.9382  0.75 6.0 2.2 7.0 5.9 2.0 6.0 0.8848 5.2 2.3 5.0 0.0963 1 6.3 2.4 7.05.9 2.1 6.0 0.4937 5.3 2.4 5.0 0.0621   1.5 6.7 2.5 7.0 6.0 2.3 6.00.2146 5.3 2.6 6.0 0.0152 2 6.6 2.6 7.0 5.9 2.7 6.0 0.2856 5.3 2.6 5.50.0330 3 6.6 2.7 7.0 5.7 2.7 5.0 0.1536 5.3 3.0 5.5 0.0486 4 6.6 2.7 7.05.4 3.0 5.0 0.0828 5.1 3.1 5.0 0.0330 5 6.6 2.8 7.0 5.3 3.1 5.0 0.07505.1 3.2 5.0 0.0326 6 6.7 2.6 7.0 5.2 3.1 5.0 0.0406 4.9 3.3 5.0 0.0138 76.7 2.6 7.0 5.1 3.2 5.0 0.0283 4.8 3.3 5.0 0.0093 8 6.6 2.7 7.0 5.2 3.25.0 0.0466 4.8 3.3 5.0 0.0126 9 6.8 2.6 7.0 5.1 3.2 5.0 0.0222 4.8 3.35.0 0.0083 10  6.9 2.5 7.0 5.1 3.3 5.0 0.0117 4.9 3.3 5.0 0.0090 11  6.92.4 7.0 5.3 3.1 5.0 0.0235 4.9 3.3 5.0 0.0057 12  6.8 2.5 7.0 5.3 3.15.0 0.0371 4.8 3.4 5.0 0.0047

Patients who received active treatment had a higher mean pain reliefscore up to 12 hours postdose compared with those who received placebo.A 5-point pain relief scale was used by patients to subjectively assesstheir level of pain relief by responding to the question “How muchrelief do you have from your starting pain?” where 0 corresponded to norelief and 4 corresponded to complete relief. As shown in Table 19, highscores were relatively consistent between the low and high dose groups.In addition, pain relief occurred earlier in the high dose group (0.75hours postdose) compared with the low dose group (4 hours postdose).TABLE 19 Pain Relief Rating for Nalbuphine 60-mg and 120-mg FormulationsCompared to Placebo Timepoint (hrs Placebo 60 mg 120 mg postdose) MeanSD Median Mean SD Median p-value* Mean SD Median p-value* 0 0.4 0.6 0.00.4 0.6 0 1.0 0.3 0.5 0 0.8665 (baseline)   0.50 0.5 0.8 0 0.6 0.8 00.7430 0.6 0.8 0 0.7200   0.75 0.5 0.9 0 0.8 0.9 1.0 0.2510 1.1 1.0 1.00.0164 1 0.5 0.9 0 0.9 1.0 1.0 0.1994 1.0 1.1 1.0 0.0431   1.5 0.4 0.8 00.8 1.0 0 0.1589 1.2 1.2 1.0 0.0027 2 0.5 0.9 0 0.9 1.1 0.0 0.1573 1.21.1 1.0 0.0035 3 0.6 1.0 0 1.1 1.2 1.0 0.0884 1.3 1.3 1.0 0.0131 4 0.61.0 0 1.2 1.3 1.0 0.0301 1.3 1.4 1.0 0.0174 5 0.6 1.0 0 1.2 1.3 1.00.0254 1.4 1.4 1.0 0.0073 6 0.5 1.0 0 1.3 1.4 1.0 0.0142 1.4 1.5 1.50.0036 7 0.5 0.9 0 1.4 1.4 1.0 0.0071 1.5 1.5 1.5 0.0017 8 0.6 1.1 0 1.41.4 1.0 0.0203 1.5 1.5 1.0 0.0091 9 0.6 1.0 0 1.3 1.4 1.0 0.0182 1.4 1.51.0 0.0079 10  0.5 0.9 0 1.4 1.5 1.0 0.0032 1.5 1.5 1.0 0.0018 11  0.50.9 0 1.3 1.4 1.0 0.0092 1.4 1.5 1.0 0.0018 12  0.5 0.8 0 1.2 1.4 1.00.0137 1.5 1.5 1.0 0.0012*Dunnett p-value comparing each treatment group with placebo at eachtimepoint

Patients were allowed to take rescue medication if needed, but wereencouraged to wait at least 2 hours before taking it. For patientsreceiving placebo, the median time to taking rescue medication was 2.3hours, compared to a median time to taking rescue medication of 3.3hours and 6.0 hours for patients receiving 60 mg and 120 mg nalbuphine,respectively. These data demonstratrate the time to ingestion of rescuemedication was significantly longer at the low and high nalbuphinedoses, respectively, compared to placebo. Moreover, the proportion ofpatients requiring rescue analgesic therapy during the 12-hour studyperiod was significantly lower with the two nalbuphine treatmentscompared to placebo: 55% of patients who received the 120 mg dose and62% of patients who received the 60 mg dose took rescue medicationwithin 12 hours of receiving treatment, compared to 88% of patients whoreceived placebo.

The percentage of patients experiencing at least a 50% reduction in painintensity was significantly higher and for the low and high nalbuphinedose groups (55% and 48% reporting a 50% reduction in pain intensity,respectively) compared to placebo (26% reporting a 50% reduction in painintensity). No unusual side effects were reported during the 12 hourdosing interval. No differences in side effect intensity among the threestudy treatments were noted at the end of the 12 hour study.

Other Embodiments

It is to be understood that while the invention has been described inconjunction with the detailed description thereof, the foregoingdescription is intended to illustrate and not limit the scope of theinvention, which is defined by the scope of the appended claims. Otheraspects, advantages, and modifications are within the scope of thefollowing claims.

1. A sustained release formulation comprising nalbuphine or apharmaceutically acceptable salt thereof and a sustained releasedelivery system, wherein the sustained release delivery system comprisesat least one hydrophilic compound, at least one cross-linking agent andat least one pharmaceutical diluent.
 2. The sustained releaseformulation of claim 1, wherein the ratio of nalbuphine or apharmaceutically acceptable salt thereof to the sustained releasedelivery system is from about 4:1 to about 1:25.
 3. The sustainedrelease formulation of claim 1, wherein the nalbuphine orpharmaceutically acceptable salt thereof is present in an amount ofabout 1 mg to about 200 mg in the formulation.
 4. The sustained releaseformulation of claim 1, wherein the sustained release delivery system ispresent in an amount of about 10 mg to about 420 mg in the formulation.5. The sustained release formulation of claim 4, wherein the at leastone hydrophilic compound is present in the sustained release deliverysystem in an amount of about 5% to about 80% by weight; the at least onecross-linking agent is present in the sustained release delivery systemin an amount of about 0.5% to about 80% by weight; and the at least onepharmaceutical diluent is present in the sustained release deliverysystem in an amount of about 20% to about 80% by weight.
 6. Thesustained release formulation of claim 1, wherein the at least onehydrophilic compound is a heteropolysaccharide gum.
 7. The sustainedrelease formulation of claim 1, wherein the at least one hydrophiliccompound is at least one compound selected from xanthan gum, tragacanthgum, a pectin, acacia, karaya, agar, carrageenan, and a gellan gum. 8.The sustained release formulation of claim 1, wherein the at least onehydrophilic compound is a xanthan gum or a derivative thereof.
 9. Thesustained release formulation of claim 1, wherein the at least onecross-linking agent is a homopolysaccharide gum.
 10. The sustainedrelease formulation of claim 1, wherein the homopolysaccharide gum is alocust bean gum or a guar gum.
 11. The sustained release formulation ofclaim 1, wherein the at least one pharmaceutical diluent is at least onecompound selected from starch, mannitol, lactose, dextrose, sucrose,microcrystalline cellulose, sorbitol, xylitol, and fructose.
 12. Thesustained release formulation of claim 1, wherein the sustained releasedelivery system further comprises a second pharmaceutical diluent. 13.The sustained release formulation of claim 12, wherein the secondpharmaceutical diluent is at least one compound selected from starch,mannitol, lactose, dextrose, sucrose, microcrystalline cellulose,sorbitol, xylitol, and fructose.
 14. The sustained release formulationof claim 1, wherein the ratio of the at least one hydrophilic compoundto the at least one cross-linking agent is from about 5:1 to about 1:5.15. The sustained release formulation of claim 1, wherein the ratio ofthe at least one pharmaceutical diluent to the at least one hydrophiliccompound is from about 9:1 to about 1:9.
 16. The sustained releaseformulation of claim 1, wherein the ratio of the nalbuphine orpharmaceutically acceptable salt thereof to the sum of the at least onehydrophilic compound and the at least one cross-linking agent is fromabout 10:1 to about 1:10.
 17. The sustained release formulation of claim1, further comprising a second hydrophilic compound.
 18. The sustainedrelease formulation of claim 17, wherein the second hydrophilic compoundis a hydroxyethyl cellulose, a hydroxypropyl cellulose, ahydroxypropylmethyl-cellulose, a carboxy methylcellulose, or a mixturethereof.
 19. A method for treating a patient suffering from paincomprising administering an effective amount of the sustained releaseformulation of claim
 1. 20. The method of claim 19, wherein the pain ischronic pain.
 21. The method of claim 19, wherein the pain isnociceptive pain, neuropathic pain, visceral pain, or idiopathic pain.22. The sustained release formulation of claim 1, wherein the sustainedrelease delivery system further comprises at least one cationiccross-linking compound.
 23. The sustained release formulation of claim22, wherein the at least one cationic cross-linking compound is presentin the sustained release delivery system in an amount of about 0.5% toabout 30% by weight.
 24. The sustained release formulation of claim 22,wherein the at least one cationic cross-linking compound is at least onecompound selected from a monovalent metal cation, a multivalent metalcation, and an inorganic salt.
 25. The sustained release formulation ofclaim 24, wherein the inorganic salt is an alkali metal sulfate, analkali metal chloride, an alkali metal borate, an alkali metal bromide,an alkali metal citrate, an alkali metal acetate, an alkali metallactate, an alkaline earth metal sulfate, an alkaline earth metalchloride, an alkaline earth metal borate, an alkaline earth metalbromide, an alkaline earth metal citrate, an alkaline earth metalacetate, an alkaline earth metal lactate, and a mixture thereof.
 26. Thesustained release formulation of claim 22, wherein the at least onecationic cross-linking compound is at least one compound selected fromcalcium sulfate, sodium chloride, potassium sulfate, sodium carbonate,lithium chloride, tripotassium phosphate, sodium borate, potassiumbromide, potassium fluoride, sodium bicarbonate, calcium chloride,magnesium chloride, sodium citrate, sodium acetate, calcium lactate,magnesium sulfate, and sodium fluoride.
 27. A method for treating apatient suffering from pain comprising administering an effective amountof the sustained release formulation of claim
 22. 28. The method ofclaim 27, wherein the pain is chronic pain.
 29. The method of claim 27,wherein the pain is nociceptive pain, neuropathic pain, visceral pain,or idiopathic pain.
 30. The sustained release formulation of claim 1,wherein the sustained release formulation has an in vitro dissolution ofabout 50% to about 100% by weight nalbuphine after about 6 hours. 31.The sustained release formulation of claim 30, wherein the sustainedrelease formulation has an in vitro dissolution of about 75% to about100% by weight nalbuphine from about 6 hours to about 8 hours.
 32. Thesustained release formulation of claim 1 wherein the sustained releaseformulation has an in vitro dissolution of about 15% to about 75% byweight nalbuphine after about 1 hour.
 33. The sustained releaseformulation of claim 1, wherein the sustained release formulation has anin vitro dissolution of about 50% by weight nalbuphine after about 1hour and about 75-100% by weight nalbuphine from about 6 hours to about8 hours.
 34. The sustained release formulation of claim 1, wherein theduration of analgesic effect of the sustained release formulation ismore than about 8 hours.
 35. The sustained release formulation of claim1, wherein the duration of analgesic effect of the sustained releaseformulation is at least about 12 hours.
 36. The sustained releaseformulation of claim 1, wherein the duration of analgesic effect of thesustained release formulation ranges from about 8 to about 12 hours. 37.A sustained release formulation comprising nalbuphine or apharmaceutically acceptable salt thereof and a sustained releasedelivery system, wherein the sustained release delivery system comprisesat least one hydrophilic compound, at least one cationic cross-linkingcompound, and at least one pharmaceutical diluent.
 38. The sustainedrelease formulation of claim 37, wherein the ratio of nalbuphine or apharmaceutically acceptable salt thereof to the sustained releasedelivery system is from about 5:1 to about 1:5.
 39. The sustainedrelease formulation of claim 37, wherein the nalbuphine orpharmaceutically acceptable salt thereof is present in an amount ofabout 1 mg to about 200 mg in the formulation.
 40. The sustained releaseformulation of claim 37, wherein the sustained release delivery systemis present in an amount of about 10 mg to about 420 mg in theformulation.
 41. The sustained release formulation of claim 37, whereinthe at least one hydrophilic compound is present in the sustainedrelease delivery system in an amount of about 5% to about 80% by weight;the at least one cationic cross-linking agent is present in thesustained release delivery system in an amount of about 0.5% to about30% by weight; and the at least one pharmaceutical diluent is present inthe sustained release delivery system in an amount of about 20% to about80% by weight.
 42. The sustained release formulation of claim 37,wherein the at least one hydrophilic compound is a heteropolysaccharidegum.
 43. The sustained release formulation of claim 37, wherein the atleast one hydrophilic compound is at least one compound selected fromxanthan gum, tragacanth gum, a pectin, acacia, karaya, agar,carrageenan, and a gellan gum.
 44. The sustained release formulation ofclaim 37, wherein the at least one hydrophilic compound is a xanthan gumor a derivative thereof.
 45. The sustained release formulation of claim37, wherein the at least one cationic cross-linking compound is at leastone compound selected from a monovalent metal cation, a multivalentmetal cation, and an inorganic salt.
 46. The sustained releaseformulation of claim 45, wherein the inorganic salt is an alkali metalsulfate, an alkali metal chloride, an alkali metal borate, an alkalimetal bromide, an alkali metal citrate, an alkali metal acetate, analkali metal lactate, an alkaline earth metal sulfate, an alkaline earthmetal chloride, an alkaline earth metal borate, an alkaline earth metalbromide, an alkaline earth metal citrate, an alkaline earth metalacetate, an alkaline earth metal lactate, and a mixture thereof.
 47. Thesustained release formulation of claim 45, wherein the at least onecationic cross-linking compound is at least one compound selected fromcalcium sulfate, sodium chloride, potassium sulfate, sodium carbonate,lithium chloride, tripotassium phosphate, sodium borate, potassiumbromide, potassium fluoride, sodium bicarbonate, calcium chloride,magnesium chloride, sodium citrate, sodium acetate, calcium lactate,magnesium sulfate, sodium fluoride, and mixtures thereof.
 48. Thesustained release formulation of claim 37, wherein the at least onepharmaceutical diluent is at least one compound selected from starch,mannitol, lactose, dextrose, sucrose, microcrystalline cellulose,sorbitol, xylitol, and fructose.
 49. The sustained release formulationof claim 37, wherein the sustained release delivery system furthercomprises a second pharmaceutical diluent.
 50. The sustained releaseformulation of claim 49, wherein the second pharmaceutical diluent is atleast one compound selected from starch, mannitol, lactose, dextrose,sucrose, microcrystalline cellulose, sorbitol, xylitol, and fructose.51. The sustained release formulation of claim 37, further comprising asecond hydrophilic compound.
 52. The sustained release formulation ofclaim 51, wherein the second hydrophilic compound is a hydroxyethylcellulose, a hydroxypropyl cellulose, a hydroxypropylmethyl-cellulose, acarboxy methylcellulose, or a mixture thereof.
 53. A method for treatinga patient suffering from pain comprising administering an effectiveamount of the sustained release formulation of claim
 37. 54. The methodof claim 53, wherein the pain is chronic pain.
 55. The method of claim53, wherein the pain is nociceptive pain, neuropathic pain, visceralpain, or idiopathic pain.
 56. The sustained release formulation of claim37, wherein the sustained release formulation has an in vitrodissolution of about 50% to about 100% by weight nalbuphine after about6 hours.
 57. The sustained release formulation of claim 56, wherein thesustained release formulation has an in vitro dissolution of about 75%to about 100% by weight nalbuphine from about 6 hours to about 8 hours.58. The sustained release formulation of claim 37 wherein the sustainedrelease formulation has an in vitro dissolution of about 15% to about75% by weight nalbuphine after about 1 hour.
 59. The sustained releaseformulation of claim 37, wherein the sustained release formulation hasan in vitro dissolution of about 50% by weight nalbuphine after about 1hour and about 75-100% by weight nalbuphine from about 6 hours to about8 hours.
 60. The sustained release formulation of claim 37, wherein theduration of analgesic effect of the sustained release formulation ismore than about 8 hours.
 61. The sustained release formulation of claim37, wherein the duration of analgesic effect of the sustained releaseformulation is at least about 12 hours.
 62. The sustained releaseformulation of claim 37, wherein the duration of analgesic effect of thesustained release formulation ranges from about 8 to about 12 hours. 63.A sustained release formulation comprising a first layer and a secondlayer, wherein the first layer comprises an immediate releaseformulation of nalbuphine or a pharmaceutically acceptable salt thereofand the second layer comprises an extended release formulation ofnalbuphine or a pharmaceutically acceptable salt thereof.
 64. Thesustained release formulation of claim 63, wherein the first layerfurther comprises a pharmaceutical disintegrant.
 65. The sustainedrelease formulation of claim 64, wherein the pharmaceutical disintegrantis at least one compound selected from croscarmellose sodium, starchglycolate, crospovidone, unmodified starch.
 66. The sustained releaseformulation of claim 63, wherein the second layer comprises nalbuphineor a pharmaceutically acceptable salt thereof and a sustained releasedelivery system, wherein the sustained release delivery system comprisesat least one hydrophilic compound, at least one cross-linking agent andat least one pharmaceutical diluent.
 67. The sustained releaseformulation of claim 66, wherein the sustained release delivery systemis present in the second layer in an amount of about 10 mg to about 420mg in the formulation.
 68. The sustained release formulation of claim66, wherein the nalbuphine or pharmaceutically acceptable salt thereofis present in the second layer in an amount of about 30 mg to about 60mg.
 69. The sustained release formulation of claim 66, wherein theweight ratio of the second layer to the first layer is about 10:1 toabout 1:10.
 70. The sustained release formulation of claim 66, whereinthe sustained release formulation has an in vitro dissolution of about18% to about 75% by weight nalbuphine after about 1 hour.
 71. Thesustained release formulation of claim 63, wherein the second layercomprises nalbuphine or a pharmaceutically acceptable salt thereof and asustained release delivery system, wherein the sustained releasedelivery system comprises at least one hydrophilic compound, at leastone cationic cross-linking agent and at least one pharmaceuticaldiluent.
 72. The sustained release formulation of claim 71, wherein thesustained release delivery system is present in the second layer in anamount of about 10 mg to about 420 mg in the formulation.
 73. Thesustained release formulation of claim 71, wherein the nalbuphine orpharmaceutically acceptable salt thereof is present in the second layerin an amount of about 30 mg to about 60 mg.
 74. The sustained releaseformulation of claim 71, wherein the weight ratio of the second layer tothe first layer is about 10:1 to about 1:10.
 75. The sustained releaseformulation of claim 71, wherein the sustained release formulation hasan in vitro dissolution of about 18% to about 75% by weight nalbuphineafter about 1 hour.
 76. A sustained release formulation comprising fromabout 5 to about 80 mg nalbuphine hydrochloride and about 80 mg to about360 mg of a sustained release delivery system; wherein the sustainedrelease delivery system comprises about 12% to 42% by weight locust beangum, about 8% to about 28% by weight xanthan gum, about 20% to about 70%by weight mannitol and about 5% to about 20% by weight calcium sulfatedihydrate.
 77. The sustained release formulation of claim 76, comprisingabout 60 mg nalbuphine hydrochloride.
 78. The sustained releaseformulation of claim 76, comprising about 30 mg to about 225 mg of asustained release delivery system.
 79. The sustained release formulationof claim 76, wherein the sustained release delivery system comprisesabout 18% locust bean gum, about 12% xanthan gum, about 60% mannitol andabout 10% calcium sulfate dihydrate.
 80. The sustained releaseformulation of claim 76, further comprising an outer coating.
 81. Amethod for treating a patient suffering from pain comprisingadministering an effective amount of the sustained release formulationof claim
 76. 82. The method of claim 81, wherein the pain is chronicpain.
 83. The method of claim 81, wherein the pain is nociceptive pain,neuropathic pain, visceral pain, or idiopathic pain.
 84. A sustainedrelease formulation comprising a first layer and a second layer, whereinthe first layer comprises from about 10 mg to about 20 mg nalbuphinehydrochloride; wherein the second layer comprises from about 45 mgnalbuphine hydrochloride and about 110 mg to about 150 mg of a sustainedrelease delivery system; wherein the sustained release delivery systemcomprises about 12% to 42% by weight locust bean gum, about 8% to about28% by weight xanthan gum, about 20% to about 70% by weight mannitol andabout 5% to about 20% by weight calcium sulfate dihydrate.
 85. Thesustained release formulation of claim 84, wherein the first layerfurther comprises a croscarmellose sodium.
 86. A method of makingsustained release formulation comprising combining nalbuphine or apharmaceutically acceptable salt thereof and a sustained releasedelivery system, wherein the sustained release delivery system comprisesat least one hydrophilic compound, at least one cross-linking agent andat least one pharmaceutical diluent.
 87. The method of claim 86, whereinthe sustained release delivery system further comprises a secondpharmaceutical diluent.
 88. The method of claim 86, wherein thesustained release delivery system further comprises at least onecationic cross-linking compound.
 89. A method of making sustainedrelease formulation comprising the steps of: a) preparing a first layer,wherein the first layer comprises nalbuphine or a pharmaceuticallyacceptable salt thereof; and b) preparing a second layer, wherein thesecond layer comprises nalbuphine or a pharmaceutically acceptable saltthereof and a sustained release delivery system, wherein the sustainedrelease delivery system comprises at least one hydrophilic compound, atleast one cross-linking agent and at least one pharmaceutical diluent;c) combining the first layer and the second layer to form a bilayerpharmaceutical composition.
 90. An oral unit dosage form comprisingnalbuphine or a pharmaceutically acceptable salt thereof, the dosageform providing an analgesic effect over a period of at least about 12hours.
 91. The oral unit dosage form of claim 90, wherein the oraldosage form provides a blood serum level of nalbuphine characterized byone or more peaks followed by plateau region.
 92. The oral unit dosageform of claim 91, wherein the plateau region has a duration of at leastabout 1 hour.
 93. The oral unit dosage form of claim 91, wherein theblood serum level of nalbuphine at each time point in the plateau regionranges from about 75% to about 125% of the mean blood serum level in theplateau region.
 94. The oral unit dosage form of claim 90 characterizedin that 75-100% of the nalbuphine is released after about 12 hours asdetermined using USP Apparatus III at 15 dpm in a pH 6.8 buffer at 37°C.
 95. An oral unit dosage form of a medicament, comprising: a uniformdosage of nalbuphine; and a sustained release delivery system,characterized in that the dosage form erodes so that nalbuphine isreleased in one or more peaks followed by a plateau region.
 96. The oralunit dosage form of claim 95, wherein the plateau region has a durationof at least about 1 hour.
 97. The oral unit dosage form of claim 95,wherein the blood serum level of nalbuphine at each time point in theplateau region ranges from about 75% to about 125% of the mean bloodserum level in the plateau region.